chr11-75566441-G-C

Position:

chr11-75566441-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_001235.5(SERPINH1):c.92G>C(p.Gly31Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 1,611,980 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00089 ( 2 hom., cov: 34)

Exomes 𝑓: 0.00086 ( 9 hom. )

Consequence

SERPINH1
NM_001235.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 2.74

Variant links:

Genes affected

SERPINH1 (HGNC:1546): (serpin family H member 1) This gene encodes a member of the serpin superfamily of serine proteinase inhibitors. The encoded protein is localized to the endoplasmic reticulum and plays a role in collagen biosynthesis as a collagen-specific molecular chaperone. Autoantibodies to the encoded protein have been found in patients with rheumatoid arthritis. Expression of this gene may be a marker for cancer, and nucleotide polymorphisms in this gene may be associated with preterm birth caused by preterm premature rupture of membranes. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, May 2011]

SERPINH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004676819).

BP6

Variant 11-75566441-G-C is Benign according to our data. Variant chr11-75566441-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290775.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.

BS2

High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINH1	NM_001235.5 link	c.92G>C	p.Gly31Ala	missense_variant	2/5	ENST00000358171.8	NP_001226.2	P50454A0A024R5K8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINH1	ENST00000358171.8 link	c.92G>C	p.Gly31Ala	missense_variant	2/5	1	NM_001235.5	ENSP00000350894.4		P50454

Frequencies

GnomAD3 genomes

AF:

0.000893

AC:

136

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.0317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00161

AC:

391

AN:

243482

Hom.:

AF XY:

0.00144

AC XY:

192

AN XY:

133110

show subpopulations

Gnomad AFR exome

AF:

0.000133

Gnomad AMR exome

AF:

0.000321

Gnomad ASJ exome

AF:

0.0328

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000375

Gnomad OTH exome

AF:

0.00218

GnomAD4 exome

AF:

0.000858

AC:

1253

AN:

1459708

Hom.:

Cov.:

AF XY:

0.000851

AC XY:

618

AN XY:

726176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000269

Gnomad4 ASJ exome

AF:

0.0306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000276

Gnomad4 OTH exome

AF:

0.00222

GnomAD4 genome

AF:

0.000893

AC:

136

AN:

152272

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.0317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00239

Alfa

AF:

0.00364

Hom.:

Bravo

AF:

0.000986

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00112

AC:

136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	SERPINH1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2020	This variant is associated with the following publications: (PMID: 30986427) -

Osteogenesis imperfecta type 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

SERPINH1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.20

T;T;.;.;T;T;T;T;.;.;.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.78

.;.;T;T;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.0047

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.0

N;N;.;.;.;.;.;N;.;.;.;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.41

N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.19

T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0010

B;B;.;.;.;B;.;B;.;.;.;.

Vest4

0.12

MVP

0.80

MPC

0.25

ClinPred

0.024

GERP RS

4.5

Varity_R

0.15

gMVP

0.53

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