1-75810755-G-T

Position:

• chr1-75810755-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002440.4(MSH4):​c.647G>T​(p.Cys216Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH4 NM_002440.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH4	NM_002440.4	c.647G>T	p.Cys216Phe	missense_variant	4/20	ENST00000263187.4	NP_002431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH4	ENST00000263187.4	c.647G>T	p.Cys216Phe	missense_variant	4/20	1	NM_002440.4	ENSP00000263187	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1438810 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 715036

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2023

The c.647G>T (p.C216F) alteration is located in exon 4 (coding exon 4) of the MSH4 gene. This alteration results from a G to T substitution at nucleotide position 647, causing the cysteine (C) at amino acid position 216 to be replaced by a phenylalanine (F). 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	0.20
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.55
Sift	Benign	0.33	T
Sift4G	Benign	0.14	T
Polyphen		0.28	B
Vest4		0.64
MutPred		0.41		Gain of helix (P = 0.0854);
MVP		0.94
MPC		0.24
ClinPred		0.93	D
GERP RS		4.6
Varity_R		0.59
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs1650173522; hg19: chr1-76276440;