5-80654678-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.439

Publications

15 publications found

Variant links:

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]

MSH3 links:

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)

DHFR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 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 VariationId is 1259457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.304 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MSH3	NM_002439.5	MANE Select	c.-50C>T	5_prime_UTR	Exon 1 of 24	NP_002430.3	P20585
DHFR	NM_000791.4	MANE Select	c.-189G>A	5_prime_UTR	Exon 1 of 6	NP_000782.1	P00374-1
DHFR	NM_001290354.2		c.-295G>A	5_prime_UTR	Exon 1 of 5	NP_001277283.1	P00374-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MSH3	ENST00000265081.7	TSL:1 MANE Select	c.-50C>T	5_prime_UTR	Exon 1 of 24	ENSP00000265081.6	P20585
DHFR	ENST00000439211.7	TSL:1 MANE Select	c.-189G>A	5_prime_UTR	Exon 1 of 6	ENSP00000396308.2	P00374-1
MSH3	ENST00000670357.1		n.-50C>T	non_coding_transcript_exon	Exon 1 of 25	ENSP00000499791.1	A0A590UKC9

Frequencies

GnomAD3 genomes

AF:

0.255

AC:

38626

AN:

151304

Hom.:

5140

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.246

AC:

43773

AN:

177808

AF XY:

0.257

show subpopulations

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 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.:

AF XY:

0.267

AC XY:

183705

AN XY:

687152

show subpopulations

African (AFR)

AF:

0.293

AC:

8395

AN:

28618

American (AMR)

AF:

0.172

AC:

6736

AN:

39166

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

6568

AN:

24304

East Asian (EAS)

AF:

0.0250

AC:

854

AN:

34142

South Asian (SAS)

AF:

0.329

AC:

26838

AN:

81584

European-Finnish (FIN)

AF:

0.186

AC:

8224

AN:

44248

Middle Eastern (MID)

AF:

0.426

AC:

2321

AN:

5446

European-Non Finnish (NFE)

AF:

0.272

AC:

289075

AN:

1064416

Other (OTH)

AF:

0.271

AC:

15498

AN:

57146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

13030

26060

39091

52121

65151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9616

19232

28848

38464

48080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.255

AC:

38652

AN:

151410

Hom.:

5146

Cov.:

AF XY:

0.252

AC XY:

18672

AN XY:

73978

show subpopulations

African (AFR)

AF:

0.281

AC:

11611

AN:

41386

American (AMR)

AF:

0.230

AC:

3505

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.291

AC:

1006

AN:

3454

East Asian (EAS)

AF:

0.0404

AC:

206

AN:

5096

South Asian (SAS)

AF:

0.318

AC:

1530

AN:

4816

European-Finnish (FIN)

AF:

0.182

AC:

1895

AN:

10420

Middle Eastern (MID)

AF:

0.340

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.266

AC:

17977

AN:

67706

Other (OTH)

AF:

0.282

AC:

593

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

1505

3009

4514

6018

7523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

406

812

1218

1624

2030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.259

Hom.:

990

Bravo

AF:

0.256

Asia WGS

AF:

0.202

AC:

701

AN:

3452

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

-0.44

PromoterAI

-0.12

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over