1-75845606-C-T

Variant names:

• chr1-75845606-C-T
• rs1498313
• NM_002440.4:c.1163-2603C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002440.4(MSH4):​c.1163-2603C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.531 in 152,008 control chromosomes in the GnomAD database, including 22,204 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (22204 hom., cov: 32)
• Consequence: MSH4 NM_002440.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.305
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002440.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH4	NM_002440.4	MANE Select	c.1163-2603C>T		intron	N/A	NP_002431.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH4	ENST00000263187.4	TSL:1 MANE Select	c.1163-2603C>T		intron	N/A	ENSP00000263187.3	O15457

Frequencies

GnomAD3 genomes AF: 0.531 AC: 80665 AN: 151890 Hom.: 22207 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.517

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.710

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.541

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.531 AC: 80681 AN: 152008 Hom.: 22204 Cov.: 32 AF XY: 0.534 AC XY: 39649 AN XY: 74298

African (AFR) AF: 0.379 AC: 15695 AN: 41444

American (AMR) AF: 0.474 AC: 7237 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 2464 AN: 3472

East Asian (EAS) AF: 0.703 AC: 3617 AN: 5144

South Asian (SAS) AF: 0.710 AC: 3423 AN: 4822

European-Finnish (FIN) AF: 0.591 AC: 6253 AN: 10578

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.592 AC: 40202 AN: 67962

Other (OTH) AF: 0.543 AC: 1150 AN: 2116

Alfa AF: 0.524 Hom.: 8306

Bravo AF: 0.514

Asia WGS AF: 0.646 AC: 2248 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.84
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1498313; hg19: chr1-76311291;