rs141721173

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001235.5(SERPINH1):c.580C>A(p.Arg194Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00122 in 1,605,100 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.00098 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

SERPINH1
NM_001235.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.71

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023349911).

BP6

Variant 11-75566929-C-A is Benign according to our data. Variant chr11-75566929-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195143.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINH1	NM_001235.5 linkuse as main transcript	c.580C>A	p.Arg194Ser	missense_variant	2/5	ENST00000358171.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINH1	ENST00000358171.8 linkuse as main transcript	c.580C>A	p.Arg194Ser	missense_variant	2/5	1	NM_001235.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000959

AC:

146

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000719

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000730

AC:

175

AN:

239694

Hom.:

AF XY:

0.000777

AC XY:

102

AN XY:

131236

show subpopulations

Gnomad AFR exome

AF:

0.000449

Gnomad AMR exome

AF:

0.000756

Gnomad ASJ exome

AF:

0.000301

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.000478

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.000499

GnomAD4 exome

AF:

0.00125

AC:

1815

AN:

1452728

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

864

AN XY:

723070

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000645

Gnomad4 NFE exome

AF:

0.00151

Gnomad4 OTH exome

AF:

0.000746

GnomAD4 genome

AF:

0.000984

AC:

150

AN:

152372

Hom.:

Cov.:

AF XY:

0.000912

AC XY:

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.000769

Gnomad4 AMR

AF:

0.000718

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00141

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00113

Hom.:

Bravo

AF:

0.000869

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000699

AC:

ExAC

AF:

0.000620

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 23, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2022	Identified by noninvasive prenatal testing in a fetus with ultrasound findings suggestive of osteogenesis imperfecta; however, a second variant was not identified and confirmation via sequencing the child's genomic DNA after birth was not performed (Malcher et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30986427, 30043834) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	SERPINH1: BP4 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 11, 2023

Variant summary: SERPINH1 c.580C>A (p.Arg194Ser) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00073 in 239694 control chromosomes. c.580C>A has been reported in the literature in individuals affected with low bone mass (Chen_2020). These reports do not provide unequivocal conclusions about association of the variant with Osteogenesis Imperfecta Type 10. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=4) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Osteogenesis imperfecta type 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Preterm premature rupture of membranes;C3151211:Osteogenesis imperfecta type 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

Cadd

Benign

Dann

Benign

0.91

DEOGEN2

Benign

0.27

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

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.79

M_CAP

Benign

0.056

MetaRNN

Benign

0.023

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

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-0.20

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

MutationTaster

Benign

0.95

D;D;D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

1.1

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

REVEL

Benign

0.21

Sift

Benign

0.73

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

Sift4G

Benign

0.085

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

Polyphen

0.013

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

Vest4

0.29

MVP

0.87

MPC

0.31

ClinPred

0.015

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.35

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