rs387906619

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 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

Publications

13 publications found

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 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 VariationId is 29673.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000791.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DHFR	NM_000791.4	MANE Select	c.238C>T	p.Leu80Phe	missense	Exon 3 of 6	NP_000782.1
DHFR	NM_001290354.2		c.82C>T	p.Leu28Phe	missense	Exon 2 of 5	NP_001277283.1
DHFR	NM_001290357.2		c.238C>T	p.Leu80Phe	missense	Exon 3 of 5	NP_001277286.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DHFR	ENST00000439211.7	TSL:1 MANE Select	c.238C>T	p.Leu80Phe	missense	Exon 3 of 6	ENSP00000396308.2
DHFR	ENST00000513048.5	TSL:1	n.246C>T		non_coding_transcript_exon	Exon 2 of 4
DHFR	ENST00000505337.5	TSL:2	c.238C>T	p.Leu80Phe	missense	Exon 3 of 7	ENSP00000426474.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000407

AC:

AN:

245614

AF XY:

0.00000751

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 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

African (AFR)

AF:

0.00

AC:

AN:

32970

American (AMR)

AF:

0.00

AC:

AN:

43508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25858

East Asian (EAS)

AF:

0.00

AC:

AN:

39478

South Asian (SAS)

AF:

0.0000237

AC:

AN:

84340

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4664

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103986

Other (OTH)

AF:

0.00

AC:

AN:

59766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000638

Hom.:

ExAC

AF:

0.00000825

AC:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Constitutional megaloblastic anemia with severe neurologic disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.0037

MutationAssessor

Uncertain

2.0

PhyloP100

4.4

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.52

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.016

Polyphen

0.99

Vest4

0.78

MutPred

0.43

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

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over