6-31743949-T-C

Position:

• chr6-31743949-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_172166.4(MSH5):​c.461T>C​(p.Phe154Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH5 NM_172166.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.14

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]

MSH5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3743472).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH5	NM_172166.4	c.461T>C	p.Phe154Ser	missense_variant	6/25	ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.461T>C	p.Phe154Ser	missense_variant	6/25	1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.461T>C		non_coding_transcript_exon_variant	6/29	1		ENSP00000417871.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.461T>C (p.F154S) alteration is located in exon 6 (coding exon 5) of the MSH5 gene. This alteration results from a T to C substitution at nucleotide position 461, causing the phenylalanine (F) at amino acid position 154 to be replaced by a serine (S). 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	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.057	T;T;.;.;.
Eigen	Benign	-0.054
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.9	L;L;.;L;L
PROVEAN	Benign	-0.51	N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.56	T;T;T;T;T
Sift4G	Benign	0.48	T;T;D;T;T
Polyphen		0.18	B;B;.;B;P
Vest4		0.70
MutPred		0.48		Gain of disorder (P = 0.0028);Gain of disorder (P = 0.0028);Gain of disorder (P = 0.0028);Gain of disorder (P = 0.0028);Gain of disorder (P = 0.0028);
MVP		0.88
MPC		0.86
ClinPred		0.77	D
GERP RS		4.7
Varity_R		0.14
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-31711726;