Variant chr5-80649393-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_000791.4(DHFR):c.238C>T(p.Leu80Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,447,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DHFR
NM_000791.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.40

Variant links:

Genes affected

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.767

PP5

Variant 5-80649393-G-A is Pathogenic according to our data. Variant chr5-80649393-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29673.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DHFR	NM_000791.4 linkuse as main transcript	c.238C>T	p.Leu80Phe	missense_variant	3/6	ENST00000439211.7
DHFR	NM_001290354.2 linkuse as main transcript	c.82C>T	p.Leu28Phe	missense_variant	2/5
DHFR	NM_001290357.2 linkuse as main transcript	c.238C>T	p.Leu80Phe	missense_variant	3/5
DHFR	NR_110936.2 linkuse as main transcript	n.682C>T		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHFR	ENST00000439211.7 linkuse as main transcript	c.238C>T	p.Leu80Phe	missense_variant	3/6	1	NM_000791.4	P1	P00374-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245614

Hom.:

AF XY:

0.00000751

AC XY:

AN XY:

133162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000342

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1447852

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720152

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00210

Hom.:

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Constitutional megaloblastic anemia with severe neurologic disease

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 11, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;D;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Uncertain

0.0037

MutationAssessor

Uncertain

2.0

M;M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0050

D;D;D;D

Sift4G

Uncertain

0.016

D;D;T;D

Polyphen

0.99

D;D;D;.

Vest4

0.78

MutPred

0.43

Gain of methylation at K81 (P = 0.0377);Gain of methylation at K81 (P = 0.0377);Gain of methylation at K81 (P = 0.0377);.;

MVP

0.89

MPC

1.4

ClinPred

0.90

GERP RS

5.4

Varity_R

0.89

gMVP

0.51

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over