14-94314305-A-T

Position:

chr14-94314305-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001756.4(SERPINA6):c.344T>A(p.Leu115His) variant causes a missense change. The variant allele was found at a frequency of 0.00246 in 1,614,130 control chromosomes in the GnomAD database, including 3 homozygotes. 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 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 2 hom. )

Consequence

SERPINA6
NM_001756.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:1

Conservation

PhyloP100: 5.41

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014943153).

BS2

High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINA6	NM_001756.4 linkuse as main transcript	c.344T>A	p.Leu115His	missense_variant	2/5	ENST00000341584.4	NP_001747.3	P08185A0A2Z4LCH4
SERPINA6	XM_047431827.1 linkuse as main transcript	c.344T>A	p.Leu115His	missense_variant	2/5		XP_047287783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SERPINA6	ENST00000341584.4 linkuse as main transcript	c.344T>A	p.Leu115His	missense_variant	2/5	1	NM_001756.4	ENSP00000342850.3	P08185
SERPINA6	ENST00000557225.1 linkuse as main transcript	c.344T>A	p.Leu115His	missense_variant	2/2	2		ENSP00000452018.1	G3V4V7
SERPINA6	ENST00000555056.1 linkuse as main transcript	n.344T>A		non_coding_transcript_exon_variant	2/5	2		ENSP00000451045.1	G3V350

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

332

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00189

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00360

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00223

AC:

560

AN:

251354

Hom.:

AF XY:

0.00244

AC XY:

332

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.00194

Gnomad NFE exome

AF:

0.00333

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00249

AC:

3638

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

1786

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00226

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00140

Gnomad4 FIN exome

AF:

0.00219

Gnomad4 NFE exome

AF:

0.00283

Gnomad4 OTH exome

AF:

0.00194

GnomAD4 genome

AF:

0.00218

AC:

332

AN:

152240

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00189

Gnomad4 NFE

AF:

0.00360

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00333

Hom.:

Bravo

AF:

0.00210

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00221

AC:

268

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00420

EpiControl

AF:

0.00468

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2024	Observed in the homozygous state or with an additional SERPINA6 variant in patients with decreased cortisol-binding activity, but has not been described in association with frank CBG deficiency (PMID: 1504007, 7061486); Published functional studies demonstrate a damaging effect with reduced cortisol binding affinity (PMID: 1504007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as L93H and CBG Leuven using alternate nomenclature; This variant is associated with the following publications: (PMID: 7061486, 1504007, 8212073, 22013108, 25010111, 30409984, 34308089, 27113851, 36681594) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2019	- -

Corticosteroid-binding globulin deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1993

- -

SERPINA6-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2023

The SERPINA6 c.344T>A variant is predicted to result in the amino acid substitution p.Leu115His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.34% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 10, 2024

Variant summary: SERPINA6 c.344T>A (p.Leu115His) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 251354 control chromosomes, predominantly at a frequency of 0.0033 within the Non-Finnish European subpopulation in the gnomAD database, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.344T>A has been reported in the literature in one individual affected with multiple diseases including diabetes mellitus, coronary artery disease, hypertension, osteoarthritis, gastric erosions secondary to the use of nonsteroidal anti-inflammatory drugs, septic shock and acute respiratory failure (Smith_1992). These report(s) do not provide unequivocal conclusions about association of the variant with Corticosteroid-Binding Globulin Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal steroid binding capacity in Chinese hamster ovary cells (Smith_1992). The following publication has been ascertained in the context of this evaluation (PMID: 1504007). ClinVar contains an entry for this variant (Variation ID: 16974). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Uncertain

0.64

D;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.038

FATHMM_MKL

Uncertain

0.89

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.015

T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.026

D;D

Sift4G

Uncertain

0.030

D;.

Polyphen

0.88

P;.

Vest4

0.47

MVP

0.90

MPC

0.31

ClinPred

0.062

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over