chr1-75892667-T-A

Variant names:

• chr1-75892667-T-A
• rs5745513
• NM_002440.4:c.2355+1843T>A

Variant summary

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

The NM_002440.4(MSH4):​c.2355+1843T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 152,252 control chromosomes in the GnomAD database, including 332 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 0.055 (332 hom., cov: 32)
• Consequence: MSH4 NM_002440.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.750
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.081 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH4	NM_002440.4	c.2355+1843T>A		intron_variant	Intron 17 of 19	ENST00000263187.4	NP_002431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH4	ENST00000263187.4	c.2355+1843T>A		intron_variant	Intron 17 of 19	1	NM_002440.4	ENSP00000263187.3

Frequencies

GnomAD3 genomes AF: 0.0551 AC: 8383 AN: 152134 Hom.: 332 Cov.: 32

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0539

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0339

Gnomad FIN AF: 0.0381

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.0829

Gnomad OTH AF: 0.0690

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

GnomAD4 genome AF: 0.0551 AC: 8383 AN: 152252 Hom.: 332 Cov.: 32 AF XY: 0.0528 AC XY: 3933 AN XY: 74432

African (AFR) AF: 0.0142 AC: 589 AN: 41554

American (AMR) AF: 0.0538 AC: 822 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 580 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0342 AC: 165 AN: 4828

European-Finnish (FIN) AF: 0.0381 AC: 404 AN: 10608

Middle Eastern (MID) AF: 0.0753 AC: 22 AN: 292

European-Non Finnish (NFE) AF: 0.0828 AC: 5635 AN: 68018

Other (OTH) AF: 0.0682 AC: 144 AN: 2110

Alfa AF: 0.0690 Hom.: 53

Bravo AF: 0.0550

Asia WGS AF: 0.0140 AC: 51 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	13
DANN	Benign	0.91
PhyloP100		0.75
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: rs5745513; hg19: chr1-76358352;