chr1-75806996-C-T

Variant names:

• chr1-75806996-C-T
• rs140872777
• NM_002440.4:c.443C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002440.4(MSH4):​c.443C>T​(p.Ala148Val) variant causes a missense change. The variant allele was found at a frequency of 0.000238 in 1,571,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A148A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: MSH4 NM_002440.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70
• Publications: 4 publications found

Genes affected

MSH4 (HGNC:7327): (mutS homolog 4) This gene encodes a member of the DNA mismatch repair mutS family. This member is a meiosis-specific protein that is not involved in DNA mismatch correction, but is required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis I. This protein and MSH5 form a heterodimer which binds uniquely to a Holliday Junction and its developmental progenitor, thus provoking ADP-ATP exchange, and stabilizing the interaction between parental chromosomes during meiosis double-stranded break repair. [provided by RefSeq, Aug 2011]

MSH4 Gene-Disease associations (from GenCC):

• premature ovarian failure 20

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005173981).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH4	NM_002440.4	c.443C>T	p.Ala148Val	missense_variant	Exon 3 of 20	ENST00000263187.4	NP_002431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH4	ENST00000263187.4	c.443C>T	p.Ala148Val	missense_variant	Exon 3 of 20	1	NM_002440.4	ENSP00000263187.3

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000239 AC: 51 AN: 213524 AF XY: 0.000163

Gnomad AFR exome AF: 0.00303

Gnomad AMR exome AF: 0.0000418

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000783

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000156 AC: 221 AN: 1419674 Hom.: 0 Cov.: 30 AF XY: 0.000138 AC XY: 97 AN XY: 705146

African (AFR) AF: 0.00235 AC: 72 AN: 30634

American (AMR) AF: 0.000117 AC: 4 AN: 34292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25040

East Asian (EAS) AF: 0.00 AC: 0 AN: 37176

South Asian (SAS) AF: 0.0000784 AC: 6 AN: 76578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53040

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5672

European-Non Finnish (NFE) AF: 0.000110 AC: 121 AN: 1098470

Other (OTH) AF: 0.000289 AC: 17 AN: 58772

GnomAD4 genome AF: 0.00101 AC: 153 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000995 AC XY: 74 AN XY: 74394

African (AFR) AF: 0.00330 AC: 137 AN: 41500

American (AMR) AF: 0.000328 AC: 5 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000392 Hom.: 0

Bravo AF: 0.00114

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000288 AC: 35

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.443C>T (p.A148V) alteration is located in exon 3 (coding exon 3) of the MSH4 gene. This alteration results from a C to T substitution at nucleotide position 443, causing the alanine (A) at amino acid position 148 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.76
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.084
Sift	Benign	0.12	T
Sift4G	Benign	0.72	T
Polyphen		0.019	B
Vest4		0.15
MVP		0.43
MPC		0.070
ClinPred		0.021	T
GERP RS		2.4
Varity_R		0.036
gMVP		0.34
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140872777; hg19: chr1-76272681;