5-80633904-T-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000791.4(DHFR):c.458A>T(p.Asp153Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,064 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D153H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DHFR
NM_000791.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 5.69

Publications

7 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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.869

PP5

Variant 5-80633904-T-A is Pathogenic according to our data. Variant chr5-80633904-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 29674.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHFR	NM_000791.4 link	c.458A>T	p.Asp153Val	missense_variant	Exon 5 of 6	ENST00000439211.7	NP_000782.1	P00374-1B0YJ76
DHFR	NM_001290354.2 link	c.302A>T	p.Asp101Val	missense_variant	Exon 4 of 5		NP_001277283.1	P00374-2
DHFR	NR_110936.2 link	n.775A>T		non_coding_transcript_exon_variant	Exon 3 of 4
DHFR	NM_001290357.2 link	c.369+3979A>T		intron_variant	Intron 4 of 4		NP_001277286.1	B4DM58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHFR	ENST00000439211.7 link	c.458A>T	p.Asp153Val	missense_variant	Exon 5 of 6	1	NM_000791.4	ENSP00000396308.2		P00374-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249832

AF XY:

0.00000738

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460064

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33412

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.00

AC:

AN:

86098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4736

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111692

Other (OTH)

AF:

0.00

AC:

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Constitutional megaloblastic anemia with severe neurologic disease

Pathogenic:2

Clinic of Pediatric and Adolescent Medicine, University Hospital Ulm

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 11, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

D;D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

.;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Pathogenic

3.3

M;M;.

PhyloP100

5.7

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-6.5

D;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.027

D;D;T

Polyphen

0.84

P;P;.

Vest4

0.65

MutPred

0.70

Gain of methylation at K156 (P = 0.086);Gain of methylation at K156 (P = 0.086);.;

MVP

0.89

MPC

0.80

ClinPred

0.94

GERP RS

5.7

Varity_R

0.86

gMVP

0.83

Mutation Taster

=8/92

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over