5-80654962-A-G

Position:

chr5-80654962-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002439.5(MSH3):c.235A>G(p.Ile79Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 1,473,312 control chromosomes in the GnomAD database, including 441,703 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I79L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.79 ( 48085 hom., cov: 29)

Exomes 𝑓: 0.77 ( 393618 hom. )

Consequence

MSH3
NM_002439.5 missense, splice_region

Scores

Splicing: ADA: 0.002496

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.243

Variant links:

Genes affected

MSH3 (HGNC:7326): (mutS homolog 3) The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer. [provided by RefSeq, Mar 2011]

MSH3 links:

DHFR (HGNC:2861): (dihydrofolate reductase) Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. While the functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless processed pseudogenes or dihydrofolate reductase-like genes have been identified on separate chromosomes. Dihydrofolate reductase deficiency has been linked to megaloblastic anemia. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

DHFR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.582627E-7).

BP6

Variant 5-80654962-A-G is Benign according to our data. Variant chr5-80654962-A-G is described in ClinVar as [Benign]. Clinvar id is 402591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-80654962-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH3	NM_002439.5 linkuse as main transcript	c.235A>G	p.Ile79Val	missense_variant, splice_region_variant	1/24	ENST00000265081.7
DHFR	NM_000791.4 linkuse as main transcript	c.-473T>C		5_prime_UTR_variant	1/6	ENST00000439211.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH3	ENST00000265081.7 linkuse as main transcript	c.235A>G	p.Ile79Val	missense_variant, splice_region_variant	1/24	1	NM_002439.5	P2
DHFR	ENST00000439211.7 linkuse as main transcript	c.-473T>C		5_prime_UTR_variant	1/6	1	NM_000791.4	P1	P00374-1
MSH3	ENST00000667069.1 linkuse as main transcript	c.235A>G	p.Ile79Val	missense_variant, splice_region_variant	1/22
MSH3	ENST00000670357.1 linkuse as main transcript	c.235A>G	p.Ile79Val	missense_variant, splice_region_variant, NMD_transcript_variant	1/25

Frequencies

GnomAD3 genomes

AF:

0.794

AC:

120111

AN:

151286

Hom.:

48045

Cov.:

show subpopulations

Gnomad AFR

AF:

0.913

Gnomad AMI

AF:

0.864

Gnomad AMR

AF:

0.764

Gnomad ASJ

AF:

0.751

Gnomad EAS

AF:

0.669

Gnomad SAS

AF:

0.696

Gnomad FIN

AF:

0.723

Gnomad MID

AF:

0.809

Gnomad NFE

AF:

0.757

Gnomad OTH

AF:

0.788

GnomAD3 exomes

AF:

0.857

AC:

68817

AN:

80302

Hom.:

30076

AF XY:

0.854

AC XY:

38527

AN XY:

45132

show subpopulations

Gnomad AFR exome

AF:

0.967

Gnomad AMR exome

AF:

0.913

Gnomad ASJ exome

AF:

0.916

Gnomad EAS exome

AF:

0.826

Gnomad SAS exome

AF:

0.836

Gnomad FIN exome

AF:

0.762

Gnomad NFE exome

AF:

0.866

Gnomad OTH exome

AF:

0.874

GnomAD4 exome

AF:

0.769

AC:

1016019

AN:

1321920

Hom.:

393618

Cov.:

AF XY:

0.768

AC XY:

500553

AN XY:

651620

show subpopulations

Gnomad4 AFR exome

AF:

0.928

Gnomad4 AMR exome

AF:

0.859

Gnomad4 ASJ exome

AF:

0.787

Gnomad4 EAS exome

AF:

0.710

Gnomad4 SAS exome

AF:

0.740

Gnomad4 FIN exome

AF:

0.750

Gnomad4 NFE exome

AF:

0.766

Gnomad4 OTH exome

AF:

0.776

GnomAD4 genome

AF:

0.794

AC:

120200

AN:

151392

Hom.:

48085

Cov.:

AF XY:

0.789

AC XY:

58349

AN XY:

73916

show subpopulations

Gnomad4 AFR

AF:

0.913

Gnomad4 AMR

AF:

0.764

Gnomad4 ASJ

AF:

0.751

Gnomad4 EAS

AF:

0.669

Gnomad4 SAS

AF:

0.695

Gnomad4 FIN

AF:

0.723

Gnomad4 NFE

AF:

0.757

Gnomad4 OTH

AF:

0.786

Alfa

AF:

0.752

Hom.:

72304

Bravo

AF:

0.806

TwinsUK

AF:

0.750

AC:

2781

ALSPAC

AF:

0.770

AC:

2967

ExAC

AF:

0.854

AC:

45364

Asia WGS

AF:

0.681

AC:

2364

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 10944853) -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 10, 2018	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Constitutional megaloblastic anemia with severe neurologic disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

8.0

DANN

Benign

0.49

DEOGEN2

Benign

0.064

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0028

LIST_S2

Benign

0.20

MetaRNN

Benign

9.6e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.48

PROVEAN

Benign

0.41

REVEL

Benign

0.24

Sift

Benign

1.0

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.028

MPC

0.024

ClinPred

0.0034

GERP RS

-4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.022

gMVP

0.087

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0025

dbscSNV1_RF

Benign

0.082

SpliceAI score (max)

0.43

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.43

Position offset: -1

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