5-80654962-A-G

Variant names:

• chr5-80654962-A-G
• rs1650697
• NM_002439.5:c.235A>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.235A>G​(p.Ile79Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 1,473,312 control chromosomes in the GnomAD database, including 441,703 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I79R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.79 (48085 hom., cov: 29)
  • Exomes 𝑓: 0.77 (393618 hom.)
• Consequence: MSH3 NM_002439.5 missense, splice_region
• Scores: Splicing: ADA: 0.002496
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.243
• Publications: 96 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.582627E-7).
• BP6: Variant 5-80654962-A-G is Benign according to our data. Variant chr5-80654962-A-G is described in ClinVar as Benign. ClinVar VariationId is 402591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.905 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.235A>G	p.Ile79Val	missense splice_region	Exon 1 of 24	NP_002430.3	P20585
	DHFR	NM_000791.4	MANE Select	c.-473T>C		5_prime_UTR	Exon 1 of 6	NP_000782.1	P00374-1
	DHFR	NM_001290354.2		c.-579T>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.235A>G	p.Ile79Val	missense splice_region	Exon 1 of 24	ENSP00000265081.6	P20585
	MSH3	ENST00000667069.1		c.235A>G	p.Ile79Val	missense splice_region	Exon 1 of 22	ENSP00000499502.1	A0A590UJN8
	DHFR	ENST00000439211.7	TSL:1 MANE Select	c.-473T>C		5_prime_UTR	Exon 1 of 6	ENSP00000396308.2	P00374-1

Frequencies

GnomAD3 genomes AF: 0.794 AC: 120111 AN: 151286 Hom.: 48045 Cov.: 29

Gnomad AFR AF: 0.913

Gnomad AMI AF: 0.864

Gnomad AMR AF: 0.764

Gnomad ASJ AF: 0.751

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.809

Gnomad NFE AF: 0.757

Gnomad OTH AF: 0.788

GnomAD2 exomes AF: 0.857 AC: 68817 AN: 80302 AF XY: 0.854

Gnomad AFR exome AF: 0.967

Gnomad AMR exome AF: 0.913

Gnomad ASJ exome AF: 0.916

Gnomad EAS exome AF: 0.826

Gnomad FIN exome AF: 0.762

Gnomad NFE exome AF: 0.866

Gnomad OTH exome AF: 0.874

GnomAD4 exome AF: 0.769 AC: 1016019 AN: 1321920 Hom.: 393618 Cov.: 28 AF XY: 0.768 AC XY: 500553 AN XY: 651620

African (AFR) AF: 0.928 AC: 25519 AN: 27504

American (AMR) AF: 0.859 AC: 19014 AN: 22146

Ashkenazi Jewish (ASJ) AF: 0.787 AC: 16719 AN: 21246

East Asian (EAS) AF: 0.710 AC: 22212 AN: 31274

South Asian (SAS) AF: 0.740 AC: 52210 AN: 70514

European-Finnish (FIN) AF: 0.750 AC: 32920 AN: 43922

Middle Eastern (MID) AF: 0.801 AC: 4103 AN: 5124

European-Non Finnish (NFE) AF: 0.766 AC: 800893 AN: 1045486

Other (OTH) AF: 0.776 AC: 42429 AN: 54704

GnomAD4 genome AF: 0.794 AC: 120200 AN: 151392 Hom.: 48085 Cov.: 29 AF XY: 0.789 AC XY: 58349 AN XY: 73916

African (AFR) AF: 0.913 AC: 37810 AN: 41418

American (AMR) AF: 0.764 AC: 11649 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.751 AC: 2603 AN: 3468

East Asian (EAS) AF: 0.669 AC: 3335 AN: 4982

South Asian (SAS) AF: 0.695 AC: 3343 AN: 4808

European-Finnish (FIN) AF: 0.723 AC: 7547 AN: 10432

Middle Eastern (MID) AF: 0.808 AC: 236 AN: 292

European-Non Finnish (NFE) AF: 0.757 AC: 51241 AN: 67730

Other (OTH) AF: 0.786 AC: 1657 AN: 2108

Alfa AF: 0.757 Hom.: 161365

Bravo AF: 0.806

TwinsUK AF: 0.750 AC: 2781

ALSPAC AF: 0.770 AC: 2967

ExAC AF: 0.854 AC: 45364

Asia WGS AF: 0.681 AC: 2364 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	1	Endometrial carcinoma;C4310719:Familial adenomatous polyposis 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.0
DANN	Benign	0.49
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	9.6e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.24
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.024
ClinPred		0.0034	T
GERP RS		-4.5
PromoterAI		0.068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.022
gMVP		0.087
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0025
dbscSNV1_RF	Benign	0.082
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.43		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1650697; hg19: chr5-79950781; COSMIC: COSV54144023; COSMIC: COSV54144023;