chr5-80654922-GCCCCCAGCT-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBA1

The NM_002439.5(MSH3):c.199_207delCCAGCTCCC(p.Pro67_Pro69del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,521,560 control chromosomes in the GnomAD database, including 63,065 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P67P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.26 ( 5185 hom., cov: 0)

Exomes 𝑓: 0.27 ( 57880 hom. )

Consequence

MSH3
NM_002439.5 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0640

Publications

10 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

DHFR links:

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ACMG classification

Classification was made for transcript

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

PM4

Nonframeshift variant in NON repetitive region in NM_002439.5.

BP6

Variant 5-80654922-GCCCCCAGCT-G is Benign according to our data. Variant chr5-80654922-GCCCCCAGCT-G is described in ClinVar as Benign. ClinVar VariationId is 402590.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	HGVSp	Effect	Exon Rank	Protein	UniProt
MSH3	NM_002439.5	MANE Select	c.199_207delCCAGCTCCC	p.Pro67_Pro69del	conservative_inframe_deletion	Exon 1 of 24	NP_002430.3	P20585
DHFR	NM_000791.4	MANE Select	c.-442_-434delAGCTGGGGG		5_prime_UTR	Exon 1 of 6	NP_000782.1	P00374-1
DHFR	NM_001290354.2		c.-548_-540delAGCTGGGGG		5_prime_UTR	Exon 1 of 5	NP_001277283.1	P00374-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MSH3	ENST00000265081.7	TSL:1 MANE Select	c.199_207delCCAGCTCCC	p.Pro67_Pro69del	conservative_inframe_deletion	Exon 1 of 24	ENSP00000265081.6	P20585
MSH3	ENST00000667069.1		c.199_207delCCAGCTCCC	p.Pro67_Pro69del	conservative_inframe_deletion	Exon 1 of 22	ENSP00000499502.1	A0A590UJN8
DHFR	ENST00000439211.7	TSL:1 MANE Select	c.-442_-434delAGCTGGGGG		5_prime_UTR	Exon 1 of 6	ENSP00000396308.2	P00374-1

Frequencies

GnomAD3 genomes

AF:

0.258

AC:

38926

AN:

150902

Hom.:

5181

Cov.:

show subpopulations

Gnomad AFR

AF:

0.282

Gnomad AMI

AF:

0.253

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.296

Gnomad EAS

AF:

0.0474

Gnomad SAS

AF:

0.317

Gnomad FIN

AF:

0.204

Gnomad MID

AF:

0.327

Gnomad NFE

AF:

0.267

Gnomad OTH

AF:

0.287

GnomAD2 exomes

AF:

0.309

AC:

39028

AN:

126454

AF XY:

0.318

show subpopulations

Gnomad AFR exome

AF:

0.443

Gnomad AMR exome

AF:

0.230

Gnomad ASJ exome

AF:

0.343

Gnomad EAS exome

AF:

0.0633

Gnomad FIN exome

AF:

0.217

Gnomad NFE exome

AF:

0.338

Gnomad OTH exome

AF:

0.350

GnomAD4 exome

AF:

0.272

AC:

373255

AN:

1370550

Hom.:

57880

AF XY:

0.276

AC XY:

187394

AN XY:

678858

show subpopulations

African (AFR)

AF:

0.321

AC:

9270

AN:

28874

American (AMR)

AF:

0.232

AC:

6906

AN:

29744

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

7046

AN:

23576

East Asian (EAS)

AF:

0.0379

AC:

1254

AN:

33128

South Asian (SAS)

AF:

0.353

AC:

27589

AN:

78140

European-Finnish (FIN)

AF:

0.219

AC:

10510

AN:

47928

Middle Eastern (MID)

AF:

0.442

AC:

2412

AN:

5458

European-Non Finnish (NFE)

AF:

0.274

AC:

292257

AN:

1066972

Other (OTH)

AF:

0.282

AC:

16011

AN:

56730

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

8992

17984

26975

35967

44959

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9658

19316

28974

38632

48290

<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:

0.258

AC:

38939

AN:

151010

Hom.:

5185

Cov.:

AF XY:

0.256

AC XY:

18875

AN XY:

73796

show subpopulations

African (AFR)

AF:

0.281

AC:

11504

AN:

40896

American (AMR)

AF:

0.231

AC:

3512

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.296

AC:

1027

AN:

3468

East Asian (EAS)

AF:

0.0474

AC:

240

AN:

5064

South Asian (SAS)

AF:

0.317

AC:

1522

AN:

4798

European-Finnish (FIN)

AF:

0.204

AC:

2142

AN:

10502

Middle Eastern (MID)

AF:

0.331

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.267

AC:

18066

AN:

67748

Other (OTH)

AF:

0.285

AC:

600

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1435

2869

4304

5738

7173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<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:

0.138

Hom.:

557

Asia WGS

AF:

0.210

AC:

730

AN:

3466

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

not provided (2)

Endometrial carcinoma;C4310719:Familial adenomatous polyposis 4 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.064

Mutation Taster

=174/126

polymorphism

(source)

Splicing

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

Publications

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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