NM_172166.4:c.1015-2207C>T

Variant names:

• chr6-31755958-C-T
• rs11754464
• NM_172166.4:c.1015-2207C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_172166.4(MSH5):​c.1015-2207C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 151,154 control chromosomes in the GnomAD database, including 5 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 0.0051 (5 hom., cov: 32)
• Consequence: MSH5 NM_172166.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.176
• Publications: 8 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00509 (769/151154) while in subpopulation EAS AF = 0.0153 (79/5178). AF 95% confidence interval is 0.0125. There are 5 homozygotes in GnomAd4. There are 410 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH5	NM_172166.4	c.1015-2207C>T		intron_variant	Intron 12 of 24	ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.1015-2207C>T		intron_variant	Intron 12 of 24	1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.1066-2207C>T		intron_variant	Intron 12 of 28	1		ENSP00000417871.2

Frequencies

GnomAD3 genomes AF: 0.00509 AC: 769 AN: 151062 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000777

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00692

Gnomad ASJ AF: 0.0361

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.000398

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.00818

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

GnomAD4 genome AF: 0.00509 AC: 769 AN: 151154 Hom.: 5 Cov.: 32 AF XY: 0.00556 AC XY: 410 AN XY: 73796

African (AFR) AF: 0.000775 AC: 32 AN: 41294

American (AMR) AF: 0.00691 AC: 105 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.0361 AC: 125 AN: 3466

East Asian (EAS) AF: 0.0153 AC: 79 AN: 5178

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4810

European-Finnish (FIN) AF: 0.000398 AC: 4 AN: 10056

Middle Eastern (MID) AF: 0.0241 AC: 7 AN: 290

European-Non Finnish (NFE) AF: 0.00494 AC: 335 AN: 67854

Other (OTH) AF: 0.00811 AC: 17 AN: 2096

Alfa AF: 0.00628 Hom.: 27

Bravo AF: 0.00524

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.3
DANN	Benign	0.77
PhyloP100		0.18

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: rs11754464; hg19: chr6-31723735;