6-31741232-A-G

Variant names:

• chr6-31741232-A-G
• rs781635576
• NM_172166.4:c.217A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_172166.4(MSH5):​c.217A>G​(p.Ile73Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,460,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MSH5 NM_172166.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0170

Genes affected

MSH5 (HGNC:7328): (mutS homolog 5) This gene encodes a member of the mutS family of proteins that are involved in DNA mismatch repair and meiotic recombination. This protein is similar to a Saccharomyces cerevisiae protein that participates in segregation fidelity and crossing-over events during meiosis. This protein plays a role in promoting ionizing radiation-induced apoptosis. This protein forms hetero-oligomers with another member of this family, mutS homolog 4. Polymorphisms in this gene have been linked to various human diseases, including IgA deficiency, common variable immunodeficiency, and premature ovarian failure. Alternative splicing results multiple transcript variants. Read-through transcription also exists between this gene and the downstream chromosome 6 open reading frame 26 (C6orf26) gene. [provided by RefSeq, Feb 2011]

MSH5-SAPCD1 (HGNC:41994): (MSH5-SAPCD1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring mutS homolog 5 (MSH5) and chromosome 6 open reading frame 26 (C6orf26) genes. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05215928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH5	NM_172166.4	c.217A>G	p.Ile73Val	missense_variant	Exon 3 of 25	ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.217A>G	p.Ile73Val	missense_variant	Exon 3 of 25	1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.217A>G		non_coding_transcript_exon_variant	Exon 3 of 29	1		ENSP00000417871.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000811 AC: 2 AN: 246726 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134460

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460774 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726702

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000847 AC: 1

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.217A>G (p.I73V) alteration is located in exon 3 (coding exon 2) of the MSH5 gene. This alteration results from a A to G substitution at nucleotide position 217, causing the isoleucine (I) at amino acid position 73 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	0.075
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.1
DANN	Benign	0.82
DEOGEN2	Benign	0.085	T;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.063	N
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.052	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.71	N;N;.;N;N
PROVEAN	Benign	-0.47	N;N;N;N;N
REVEL	Benign	0.0090
Sift	Benign	0.25	T;T;T;T;T
Sift4G	Benign	0.71	T;T;T;T;T
Polyphen		0.0010	B;B;.;B;B
Vest4		0.088
MVP		0.20
MPC		0.37
ClinPred		0.019	T
GERP RS		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.22

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

Other links and lift over

dbSNP: rs781635576; hg19: chr6-31709009;