5-80654678-C-T

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.-50C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,530,480 control chromosomes in the GnomAD database, including 56,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5146 hom., cov: 31)
  • Exomes 𝑓: 0.26 (51053 hom.)
• Consequence: MSH3 NM_002439.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.439

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=-0.67).
• BP6: Variant 5-80654678-C-T is Benign according to our data. Variant chr5-80654678-C-T is described in ClinVar as [Benign]. Clinvar id is 1259457.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHFR	NM_000791.4	c.-189G>A		5_prime_UTR_variant	1/6	ENST00000439211.7
MSH3	NM_002439.5	c.-50C>T		5_prime_UTR_variant	1/24	ENST00000265081.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH3	ENST00000265081.7	c.-50C>T		5_prime_UTR_variant	1/24	1	NM_002439.5	P2
DHFR	ENST00000439211.7	c.-189G>A		5_prime_UTR_variant	1/6	1	NM_000791.4	P1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38626 AN: 151304 Hom.: 5140 Cov.: 31

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0405

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.333

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.283

GnomAD3 exomes AF: 0.246 AC: 43773 AN: 177808 Hom.: 6072 AF XY: 0.257 AC XY: 25770 AN XY: 100388

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.267

Gnomad EAS exome AF: 0.0391

Gnomad SAS exome AF: 0.338

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.281

GnomAD4 exome AF: 0.264 AC: 364509 AN: 1379070 Hom.: 51053 Cov.: 24 AF XY: 0.267 AC XY: 183705 AN XY: 687152

Gnomad4 AFR exome AF: 0.293

Gnomad4 AMR exome AF: 0.172

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.0250

Gnomad4 SAS exome AF: 0.329

Gnomad4 FIN exome AF: 0.186

Gnomad4 NFE exome AF: 0.272

Gnomad4 OTH exome AF: 0.271

GnomAD4 genome AF: 0.255 AC: 38652 AN: 151410 Hom.: 5146 Cov.: 31 AF XY: 0.252 AC XY: 18672 AN XY: 73978

Gnomad4 AFR AF: 0.281

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.291

Gnomad4 EAS AF: 0.0404

Gnomad4 SAS AF: 0.318

Gnomad4 FIN AF: 0.182

Gnomad4 NFE AF: 0.266

Gnomad4 OTH AF: 0.282

Alfa AF: 0.259 Hom.: 957

Bravo AF: 0.256

Asia WGS AF: 0.202 AC: 701 AN: 3452

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	12
Dann	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2250063; hg19: chr5-79950497; COSMIC: COSV54150169; COSMIC: COSV54150169;