chr1-75799103-T-C

Variant names:

• chr1-75799103-T-C
• rs1146644
• NM_002440.4:c.244+1874T>C

Variant summary

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

The NM_002440.4(MSH4):​c.244+1874T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 152,056 control chromosomes in the GnomAD database, including 28,279 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 0.59 (28279 hom., cov: 32)
• Consequence: MSH4 NM_002440.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.826
• Publications: 14 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH4	NM_002440.4	c.244+1874T>C		intron_variant	Intron 1 of 19	ENST00000263187.4	NP_002431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH4	ENST00000263187.4	c.244+1874T>C		intron_variant	Intron 1 of 19	1	NM_002440.4	ENSP00000263187.3

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90417 AN: 151938 Hom.: 28269 Cov.: 32

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.0461

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.615

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

GnomAD4 genome AF: 0.595 AC: 90454 AN: 152056 Hom.: 28279 Cov.: 32 AF XY: 0.588 AC XY: 43710 AN XY: 74328

African (AFR) AF: 0.728 AC: 30168 AN: 41458

American (AMR) AF: 0.560 AC: 8565 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 2192 AN: 3468

East Asian (EAS) AF: 0.0462 AC: 239 AN: 5178

South Asian (SAS) AF: 0.414 AC: 1993 AN: 4818

European-Finnish (FIN) AF: 0.565 AC: 5970 AN: 10566

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.580 AC: 39450 AN: 67974

Other (OTH) AF: 0.619 AC: 1306 AN: 2110

Alfa AF: 0.590 Hom.: 5471

Bravo AF: 0.600

Asia WGS AF: 0.325 AC: 1131 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.31
DANN	Benign	0.68
PhyloP100		-0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1146644; hg19: chr1-76264788;