Genetic Variant DHFR:p.Glu184Val (chr5-80629100-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000791.4(DHFR):c.551A>T(p.Glu184Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E184K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

DHFR
NM_000791.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.36

Publications

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

DHFR links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41511917).

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	UniProt
DHFR	NM_000791.4	MANE Select	c.551A>T	p.Glu184Val	missense	Exon 6 of 6	NP_000782.1	P00374-1
DHFR	NM_001290354.2		c.395A>T	p.Glu132Val	missense	Exon 5 of 5	NP_001277283.1	P00374-2
DHFR	NM_001290357.2		c.*45A>T		3_prime_UTR	Exon 5 of 5	NP_001277286.1	B4DM58

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DHFR	ENST00000439211.7	TSL:1 MANE Select	c.551A>T	p.Glu184Val	missense	Exon 6 of 6	ENSP00000396308.2	P00374-1
DHFR	ENST00000513048.5	TSL:1	n.432A>T		non_coding_transcript_exon	Exon 4 of 4
DHFR	ENST00000505337.5	TSL:2	c.551A>T	p.Glu184Val	missense	Exon 6 of 7	ENSP00000426474.1	P00374-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.083

MetaRNN

Benign

0.42

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.9

PhyloP100

5.4

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Polyphen

0.31

Vest4

0.41

MutPred

0.54

Loss of disorder (P = 0.0149)

MVP

0.86

MPC

0.91

ClinPred

0.98

GERP RS

5.1

Varity_R

0.75

gMVP

0.79

Mutation Taster

=53/47

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over