6-31739953-T-C

Variant names:

• chr6-31739953-T-C
• rs3131382
• ENST00000375755.8:c.-281T>C

Variant summary

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

The ENST00000375755.8(MSH5):​c.-281T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.956 in 152,700 control chromosomes in the GnomAD database, including 69,859 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 0.96 (69686 hom., cov: 34)
  • Exomes 𝑓: 0.97 (173 hom.)
• Consequence: MSH5 ENST00000375755.8 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 20 publications found

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]

CLIC1 (HGNC:2062): (chloride intracellular channel 1) Chloride channels are a diverse group of proteins that regulate fundamental cellular processes including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, and regulation of cell volume. Chloride intracellular channel 1 is a member of the p64 family; the protein localizes principally to the cell nucleus and exhibits both nuclear and plasma membrane chloride ion channel activity. [provided by RefSeq, Jul 2008]

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 (EAS) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH5	NM_172166.4	c.-123T>C		upstream_gene_variant		ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.-123T>C		upstream_gene_variant		1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.-123T>C		upstream_gene_variant		1		ENSP00000417871.2

Frequencies

GnomAD3 genomes AF: 0.956 AC: 145518 AN: 152216 Hom.: 69622 Cov.: 34

Gnomad AFR AF: 0.986

Gnomad AMI AF: 0.933

Gnomad AMR AF: 0.973

Gnomad ASJ AF: 0.991

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.925

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.930

Gnomad OTH AF: 0.976

GnomAD4 exome AF: 0.973 AC: 356 AN: 366 Hom.: 173 Cov.: 0 AF XY: 0.988 AC XY: 245 AN XY: 248

African (AFR) AF: 1.00 AC: 8 AN: 8

American (AMR) AF: 1.00 AC: 6 AN: 6

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 6 AN: 6

East Asian (EAS) AF: 1.00 AC: 4 AN: 4

South Asian (SAS) AF: 1.00 AC: 188 AN: 188

European-Finnish (FIN) AF: 0.833 AC: 10 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.937 AC: 118 AN: 126

Other (OTH) AF: 1.00 AC: 16 AN: 16

GnomAD4 genome AF: 0.956 AC: 145641 AN: 152334 Hom.: 69686 Cov.: 34 AF XY: 0.957 AC XY: 71249 AN XY: 74486

African (AFR) AF: 0.986 AC: 41005 AN: 41576

American (AMR) AF: 0.973 AC: 14901 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.991 AC: 3442 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5171 AN: 5172

South Asian (SAS) AF: 1.00 AC: 4833 AN: 4834

European-Finnish (FIN) AF: 0.925 AC: 9815 AN: 10612

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.930 AC: 63264 AN: 68032

Other (OTH) AF: 0.976 AC: 2065 AN: 2116

Alfa AF: 0.944 Hom.: 148792

Bravo AF: 0.960

Asia WGS AF: 0.997 AC: 3466 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	12
DANN	Benign	0.77
PhyloP100		1.1
PromoterAI		0.092	Neutral
Mutation Taster		=300/0	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: rs3131382; hg19: chr6-31707730;