11-75566446-G-C

Position:

chr11-75566446-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001235.5(SERPINH1):c.97G>C(p.Ala33Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000788 in 1,612,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00040 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

SERPINH1
NM_001235.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.581

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 -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0152722895).

BP6

Variant 11-75566446-G-C is Benign according to our data. Variant chr11-75566446-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 993904.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINH1	NM_001235.5 link	c.97G>C	p.Ala33Pro	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.97G>C	p.Ala33Pro	missense_variant	2/5	1	NM_001235.5	ENSP00000350894.4		P50454

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000123

AC:

AN:

244194

Hom.:

AF XY:

0.0000900

AC XY:

AN XY:

133388

show subpopulations

Gnomad AFR exome

AF:

0.00171

Gnomad AMR exome

AF:

0.0000876

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1459870

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

726238

show subpopulations

Gnomad4 AFR exome

AF:

0.00170

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000400

AC:

AN:

152390

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74524

show subpopulations

Gnomad4 AFR

AF:

0.00144

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.000506

ESP6500AA

AF:

0.00205

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 01, 2020	The SERPINH1 c.97G>C; p.Ala33Pro variant (rs150061926), to our knowledge, is not reported in the medical literature or gene specific databases. However, ARUP Laboratories has detected this variant in an individual with an alternative molecular explanation for disease. The variant is listed in the African population with an allele frequency of 0.13% (32/23,940 alleles) in the Genome Aggregation Database. The alanine at codon 33 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Ala33Pro variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

3.8

DANN

Benign

0.87

DEOGEN2

Benign

0.20

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.31

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

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.015

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

MetaSVM

Benign

-0.61

MutationAssessor

Benign

0.0

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

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.28

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

REVEL

Benign

0.18

Sift

Benign

0.16

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

Sift4G

Benign

0.19

T;T;T;T;D;T;T;T;T;T;T;T

Polyphen

0.61

P;P;.;.;.;B;.;P;.;.;.;.

Vest4

0.20

MVP

0.74

MPC

0.30

ClinPred

0.0032

GERP RS

-0.71

Varity_R

0.15

gMVP

0.44

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