5-80654689-C-T

Variant names:

• chr5-80654689-C-T
• rs1105525
• NM_002439.5:c.-39C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002439.5(MSH3):​c.-39C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,560,524 control chromosomes in the GnomAD database, including 23,414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1639 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21775 hom.)
• Consequence: MSH3 NM_002439.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00800
• Publications: 20 publications found

Genes affected

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]

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]

DHFR Gene-Disease associations (from GenCC):

• constitutional megaloblastic anemia with severe neurologic disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-80654689-C-T is Benign according to our data. Variant chr5-80654689-C-T is described in ClinVar as Benign. ClinVar VariationId is 1220684.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.-39C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 24	ENST00000265081.7	NP_002430.3
MSH3	NM_002439.5	c.-39C>T		5_prime_UTR_variant	Exon 1 of 24	ENST00000265081.7	NP_002430.3
DHFR	NM_000791.4	c.-200G>A		5_prime_UTR_variant	Exon 1 of 6	ENST00000439211.7	NP_000782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.-39C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 24	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000670357.1	n.-39C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 25			ENSP00000499791.1
MSH3	ENST00000670357.1	n.-39C>T		non_coding_transcript_exon_variant	Exon 1 of 25			ENSP00000499791.1
MSH3	ENST00000265081.7	c.-39C>T		5_prime_UTR_variant	Exon 1 of 24	1	NM_002439.5	ENSP00000265081.6
DHFR	ENST00000439211.7	c.-200G>A		5_prime_UTR_variant	Exon 1 of 6	1	NM_000791.4	ENSP00000396308.2
MSH3	ENST00000670357.1	n.-39C>T		5_prime_UTR_variant	Exon 1 of 25			ENSP00000499791.1
MSH3	ENST00000667069.1	c.-39C>T		upstream_gene_variant				ENSP00000499502.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20264 AN: 151422 Hom.: 1639 Cov.: 32

Gnomad AFR AF: 0.0478

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0677

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.156 AC: 30664 AN: 196436 AF XY: 0.166

Gnomad AFR exome AF: 0.0442

Gnomad AMR exome AF: 0.0786

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.0686

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.169 AC: 238344 AN: 1408996 Hom.: 21775 Cov.: 26 AF XY: 0.172 AC XY: 120785 AN XY: 701824

African (AFR) AF: 0.0413 AC: 1216 AN: 29434

American (AMR) AF: 0.0844 AC: 3482 AN: 41276

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3132 AN: 24920

East Asian (EAS) AF: 0.0672 AC: 2372 AN: 35278

South Asian (SAS) AF: 0.240 AC: 19961 AN: 83192

European-Finnish (FIN) AF: 0.201 AC: 9175 AN: 45594

Middle Eastern (MID) AF: 0.134 AC: 751 AN: 5606

European-Non Finnish (NFE) AF: 0.174 AC: 189290 AN: 1085462

Other (OTH) AF: 0.154 AC: 8965 AN: 58234

GnomAD4 genome AF: 0.134 AC: 20272 AN: 151528 Hom.: 1639 Cov.: 32 AF XY: 0.136 AC XY: 10053 AN XY: 74026

African (AFR) AF: 0.0478 AC: 1979 AN: 41438

American (AMR) AF: 0.113 AC: 1720 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 438 AN: 3466

East Asian (EAS) AF: 0.0677 AC: 346 AN: 5108

South Asian (SAS) AF: 0.242 AC: 1161 AN: 4804

European-Finnish (FIN) AF: 0.206 AC: 2147 AN: 10438

Middle Eastern (MID) AF: 0.124 AC: 36 AN: 290

European-Non Finnish (NFE) AF: 0.178 AC: 12077 AN: 67732

Other (OTH) AF: 0.112 AC: 237 AN: 2108

Alfa AF: 0.103 Hom.: 291

Bravo AF: 0.117

Asia WGS AF: 0.134 AC: 463 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.2
DANN	Benign	0.84
PhyloP100		-0.0080
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=297/3	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: rs1105525; hg19: chr5-79950508; COSMIC: COSV54143671; COSMIC: COSV54143671;