5-80654693-A-G

Variant names:

• chr5-80654693-A-G
• rs1105524
• NM_002439.5:c.-35A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.89
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1237508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002439.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	NM_002439.5	MANE Select	c.-35A>G		5_prime_UTR	Exon 1 of 24	NP_002430.3	P20585
	DHFR	NM_000791.4	MANE Select	c.-204T>C		5_prime_UTR	Exon 1 of 6	NP_000782.1	P00374-1
	DHFR	NM_001290354.2		c.-310T>C		5_prime_UTR	Exon 1 of 5	NP_001277283.1	P00374-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	ENST00000265081.7	TSL:1 MANE Select	c.-35A>G		5_prime_UTR	Exon 1 of 24	ENSP00000265081.6	P20585
	DHFR	ENST00000439211.7	TSL:1 MANE Select	c.-204T>C		5_prime_UTR	Exon 1 of 6	ENSP00000396308.2	P00374-1
	MSH3	ENST00000670357.1		n.-35A>G		non_coding_transcript_exon	Exon 1 of 25	ENSP00000499791.1	A0A590UKC9

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

GnomAD2 exomes AF: 0.636 AC: 125777 AN: 197686 AF XY: 0.649

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 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

African (AFR) AF: 0.936 AC: 27613 AN: 29488

American (AMR) AF: 0.512 AC: 20973 AN: 40932

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 15585 AN: 24848

East Asian (EAS) AF: 0.369 AC: 12857 AN: 34816

South Asian (SAS) AF: 0.758 AC: 63168 AN: 83298

European-Finnish (FIN) AF: 0.635 AC: 29145 AN: 45896

Middle Eastern (MID) AF: 0.802 AC: 4494 AN: 5606

European-Non Finnish (NFE) AF: 0.668 AC: 725202 AN: 1085420

Other (OTH) AF: 0.673 AC: 39155 AN: 58156

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

African (AFR) AF: 0.919 AC: 38058 AN: 41414

American (AMR) AF: 0.631 AC: 9584 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.635 AC: 2193 AN: 3456

East Asian (EAS) AF: 0.392 AC: 1967 AN: 5016

South Asian (SAS) AF: 0.751 AC: 3611 AN: 4810

European-Finnish (FIN) AF: 0.643 AC: 6622 AN: 10298

Middle Eastern (MID) AF: 0.733 AC: 211 AN: 288

European-Non Finnish (NFE) AF: 0.667 AC: 45106 AN: 67648

Other (OTH) AF: 0.721 AC: 1517 AN: 2104

Alfa AF: 0.621 Hom.: 3427

Bravo AF: 0.723

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.84
DANN	Benign	0.49
PhyloP100		-4.9
PromoterAI		-0.14	Neutral
Mutation Taster		=299/1	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: rs1105524; hg19: chr5-79950512; COSMIC: COSV54143681; COSMIC: COSV54143681;