14-94304471-C-T

Position:

• chr14-94304471-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 3.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 16975.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr14-94304471-C-T is described in UniProt as null. Variant chr14-94304471-C-T is described in Lovd as [Pathogenic].
• 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/exons	MANE	Protein	UniProt
SERPINA6	NM_001756.4	c.1165G>A	p.Asp389Asn	missense_variant	5/5	ENST00000341584.4	NP_001747.3
SERPINA6	XM_047431827.1	c.1336G>A	p.Asp446Asn	missense_variant	5/5		XP_047287783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINA6	ENST00000341584.4	c.1165G>A	p.Asp389Asn	missense_variant	5/5	1	NM_001756.4	ENSP00000342850.3
SERPINA6	ENST00000555056.1	n.*477G>A		non_coding_transcript_exon_variant	5/5	2		ENSP00000451045.1
SERPINA6	ENST00000555056.1	n.*477G>A		3_prime_UTR_variant	5/5	2		ENSP00000451045.1

Frequencies

GnomAD3 genomes AF: 0.000507 AC: 77 AN: 152000 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000617 AC: 155 AN: 251322 Hom.: 0 AF XY: 0.000567 AC XY: 77 AN XY: 135852

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 SAS exome AF: 0.0000653

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.: 0 Cov.: 31 AF XY: 0.000355 AC XY: 258 AN XY: 727248

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.00704

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000190

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74368

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000483 Hom.: 0

Bravo AF: 0.000612

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Corticosteroid-binding globulin deficiency Pathogenic:3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 12, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 26, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 30, 2020	- -

SERPINA6-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2024

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	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.088
Eigen_PC	Benign	-0.18
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.52
Sift	Benign	0.37	T
Sift4G	Benign	0.15	T
Polyphen		0.98	D
Vest4		0.36
MVP		0.91
MPC		0.45
ClinPred		0.17	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.73
gMVP		0.68

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

LitVar

Other links and lift over

dbSNP: rs28929488; hg19: chr14-94770808;