5-80633904-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

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).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DHFR NM_000791.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 5.69

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 id is 29674.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHFR	NM_000791.4	c.458A>T	p.Asp153Val	missense_variant	5/6	ENST00000439211.7
DHFR	NM_001290354.2	c.302A>T	p.Asp101Val	missense_variant	4/5
DHFR	NM_001290357.2	c.369+3979A>T		intron_variant
DHFR	NR_110936.2	n.775A>T		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHFR	ENST00000439211.7	c.458A>T	p.Asp153Val	missense_variant	5/6	1	NM_000791.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249832 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135508

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: 0.00

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: 1 AN: 1460064 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726370

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Constitutional megaloblastic anemia with severe neurologic disease Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Clinic of Pediatric and Adolescent Medicine, University Hospital Ulm	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 11, 2011	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.3	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.50	T
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	D
GERP RS		5.7
Varity_R		0.86
gMVP		0.83

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

Other links and lift over

dbSNP: rs121913223; hg19: chr5-79929723;