14-94304471-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BP4

The NM_001756.4(SERPINA6):c.1165G>A(p.Asp389Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000358 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

SERPINA6
NM_001756.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 3.96

Publications

17 publications found

Variant links:

Genes affected

SERPINA6 (HGNC:1540): (serpin family A member 6) This gene encodes an alpha-globulin protein with corticosteroid-binding properties. This is the major transport protein for glucorticoids and progestins in the blood of most vertebrates. The gene localizes to a chromosomal region containing several closely related serine protease inhibitors which may have evolved by duplication events. [provided by RefSeq, Jul 2008]

SERPINA6 Gene-Disease associations (from GenCC):

corticosteroid-binding globulin deficiency
Inheritance: SD, Unknown, AD, AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

SERPINA6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant 14-94304471-C-T is Pathogenic according to our data. Variant chr14-94304471-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16975.

BP4

Computational evidence support a benign effect (MetaRNN=0.013436496). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA6	NM_001756.4 link	c.1165G>A	p.Asp389Asn	missense_variant	Exon 5 of 5	ENST00000341584.4	NP_001747.3
SERPINA6	XM_047431827.1 link	c.1336G>A	p.Asp446Asn	missense_variant	Exon 5 of 5		XP_047287783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SERPINA6	ENST00000341584.4 link	c.1165G>A	p.Asp389Asn	missense_variant	Exon 5 of 5	1	NM_001756.4	ENSP00000342850.3
SERPINA6	ENST00000555056.1 link	n.*477G>A		non_coding_transcript_exon_variant	Exon 5 of 5	2		ENSP00000451045.1
SERPINA6	ENST00000555056.1 link	n.*477G>A		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000451045.1

Frequencies

GnomAD3 genomes

AF:

0.000507

AC:

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000617

AC:

155

AN:

251322

AF XY:

0.000567

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00784

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000343

AC:

501

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000355

AC XY:

258

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33480

American (AMR)

AF:

0.000715

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00704

AC:

184

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000190

AC:

211

AN:

1112010

Other (OTH)

AF:

0.000778

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000506

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000471

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41482

American (AMR)

AF:

0.00183

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

67992

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000477

Hom.:

Bravo

AF:

0.000612

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000511

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Corticosteroid-binding globulin deficiency

Pathogenic:4Uncertain:2

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

NM_001756.3:c.1165G>A in the SERPINA6 gene has an allele frequency of 0.007 in Ashkenazi Jewish subpopulation in the gnomAD database. It was detected in individual with autosomal recessive Corticosteroid-binding globulin deficiency, two homozygous c.1165G>A(PMID: 12780753; 20610591). Co-segregation evidence in a pedigree, two patients were affected and one sibling unaffected (PMID: 20610591). Pathogenic computational verdict because 9 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster and REVEL. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PP1_Moderate; PM3; PP4; PP3. -

Jan 30, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 26, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 26, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 12, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

SERPINA6-related disorder

Pathogenic:1

Sep 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SERPINA6 c.1165G>A variant is predicted to result in the amino acid substitution p.Asp389Asn. This variant, also referred to as CBG Lyon or p.Asp367Asn, has been reported in the heterozygous and homozygous state in individuals with corticosteroid-binding globulin (CBG) deficiency (Emptoz-Bonneton et al. 2000. PubMed ID: 10634411; Brunner et al. 2003. PubMed ID: 12780753; Cizza et al. 2011. PubMed ID: 21795453). Functional studies found this variant resulted in reduced affinity for cortisol and results in low or low-normal serum cortisol levels in homozygous and heterozygous subjects (Emptoz-Bonneton et al. 2000. PubMed ID: 10634411; Brunner et al. 2003. PubMed ID: 12780753; Cizza et al. 2011. PubMed ID: 21795453). This variant is reported in 0.77% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. In ClinVar this variant has conflicting interpretations of pathogenicity of uncertain, likely pathogenic, and pathogenic (https://ncbi.nlm.nih.gov/clinvar/variation/16975/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Benign

-0.088

Eigen_PC

Benign

-0.18

FATHMM_MKL

Pathogenic

0.97

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.2

PhyloP100

4.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.52

Sift

Benign

0.37

Sift4G

Benign

0.15

Polyphen

0.98

Vest4

0.36

MVP

0.91

MPC

0.45

ClinPred

0.17

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.73

gMVP

0.68

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over