Genetic Variant DHFR:p.Leu167Leu (chr5-80629150-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_001290357.2(DHFR):c.385C>G(p.Leu129Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L129F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

DHFR
NM_001290357.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.479

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

DHFR links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12485331).

BP6

Variant 5-80629150-G-C is Benign according to our data. Variant chr5-80629150-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2717847.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290357.2. 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.501C>G	p.Leu167Leu	synonymous	Exon 6 of 6	NP_000782.1	P00374-1
DHFR	NM_001290357.2		c.385C>G	p.Leu129Val	missense	Exon 5 of 5	NP_001277286.1	B4DM58
DHFR	NM_001290354.2		c.345C>G	p.Leu115Leu	synonymous	Exon 5 of 5	NP_001277283.1	P00374-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DHFR	ENST00000439211.7	TSL:1 MANE Select	c.501C>G	p.Leu167Leu	synonymous	Exon 6 of 6	ENSP00000396308.2	P00374-1
DHFR	ENST00000513048.5	TSL:1	n.382C>G		non_coding_transcript_exon	Exon 4 of 4
DHFR	ENST00000511032.5	TSL:2	c.385C>G	p.Leu129Val	missense	Exon 5 of 5	ENSP00000422732.1	B4DM58

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

5.5

(source)

DANN

Benign

0.93

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.35

M_CAP

Benign

0.033

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.96

PhyloP100

0.48

PROVEAN

Benign

0.040

REVEL

Benign

0.038

Sift

Pathogenic

0.0

Sift4G

Benign

0.076

Polyphen

0.12

Vest4

0.096

MutPred

0.42

Gain of MoRF binding (P = 0.0769)

MVP

0.70

ClinPred

0.091

GERP RS

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=96/4

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