5-80654693-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002439.5(MSH3):c.-35A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.672 in 1,559,588 control chromosomes in the GnomAD database, including 357,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.72 (41001 hom., cov: 31)
  • Exomes 𝑓: 0.67 (316748 hom.)
• Consequence: MSH3 NM_002439.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.89

Genes affected

DHFR (HGNC:2861): (dihydrofolate reductase) Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. While the functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless processed pseudogenes or dihydrofolate reductase-like genes have been identified on separate chromosomes. Dihydrofolate reductase deficiency has been linked to megaloblastic anemia. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

MSH3 (HGNC:7326): (mutS homolog 3) The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 5-80654693-A-G is Benign according to our data. Variant chr5-80654693-A-G is described in ClinVar as [Benign]. Clinvar id is 1237508.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHFR	NM_000791.4	c.-204T>C		5_prime_UTR_variant	1/6	ENST00000439211.7
MSH3	NM_002439.5	c.-35A>G		5_prime_UTR_variant	1/24	ENST00000265081.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH3	ENST00000265081.7	c.-35A>G		5_prime_UTR_variant	1/24	1	NM_002439.5	P2
DHFR	ENST00000439211.7	c.-204T>C		5_prime_UTR_variant	1/6	1	NM_000791.4	P1

Frequencies

GnomAD3 genomes AF: 0.724 AC: 109393 AN: 151020 Hom.: 40944 Cov.: 31

Gnomad AFR AF: 0.919

Gnomad AMI AF: 0.706

Gnomad AMR AF: 0.631

Gnomad ASJ AF: 0.635

Gnomad EAS AF: 0.393

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.643

Gnomad MID AF: 0.719

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.721

GnomAD3 exomes AF: 0.636 AC: 125777 AN: 197686 Hom.: 41559 AF XY: 0.649 AC XY: 72089 AN XY: 111006

Gnomad AFR exome AF: 0.925

Gnomad AMR exome AF: 0.487

Gnomad ASJ exome AF: 0.614

Gnomad EAS exome AF: 0.359

Gnomad SAS exome AF: 0.761

Gnomad FIN exome AF: 0.630

Gnomad NFE exome AF: 0.661

Gnomad OTH exome AF: 0.660

GnomAD4 exome AF: 0.666 AC: 938192 AN: 1408460 Hom.: 316748 Cov.: 27 AF XY: 0.670 AC XY: 469696 AN XY: 701412

Gnomad4 AFR exome AF: 0.936

Gnomad4 AMR exome AF: 0.512

Gnomad4 ASJ exome AF: 0.627

Gnomad4 EAS exome AF: 0.369

Gnomad4 SAS exome AF: 0.758

Gnomad4 FIN exome AF: 0.635

Gnomad4 NFE exome AF: 0.668

Gnomad4 OTH exome AF: 0.673

GnomAD4 genome AF: 0.725 AC: 109506 AN: 151128 Hom.: 41001 Cov.: 31 AF XY: 0.721 AC XY: 53205 AN XY: 73750

Gnomad4 AFR AF: 0.919

Gnomad4 AMR AF: 0.631

Gnomad4 ASJ AF: 0.635

Gnomad4 EAS AF: 0.392

Gnomad4 SAS AF: 0.751

Gnomad4 FIN AF: 0.643

Gnomad4 NFE AF: 0.667

Gnomad4 OTH AF: 0.721

Alfa AF: 0.621 Hom.: 3427

Bravo AF: 0.723

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.84
Dann	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs1105524; hg19: chr5-79950512; COSMIC: COSV54143681; COSMIC: COSV54143681;