rs1191351549

Variant names:

• chr5-80629100-T-A
• rs1191351549
• NM_000791.4:c.551A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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 (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DHFR NM_000791.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.36

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41511917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHFR	NM_000791.4	c.551A>T	p.Glu184Val	missense_variant	Exon 6 of 6	ENST00000439211.7	NP_000782.1
DHFR	NM_001290354.2	c.395A>T	p.Glu132Val	missense_variant	Exon 5 of 5		NP_001277283.1
DHFR	NM_001290357.2	c.*45A>T		3_prime_UTR_variant	Exon 5 of 5		NP_001277286.1
DHFR	NR_110936.2	n.868A>T		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHFR	ENST00000439211.7	c.551A>T	p.Glu184Val	missense_variant	Exon 6 of 6	1	NM_000791.4	ENSP00000396308.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.551A>T (p.E184V) alteration is located in exon 6 (coding exon 6) of the DHFR gene. This alteration results from a A to T substitution at nucleotide position 551, causing the glutamic acid (E) at amino acid position 184 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;D;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.9	L;L;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0080	D;D;T
Polyphen		0.31	B;B;.
Vest4		0.41
MutPred		0.54		Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);.;
MVP		0.86
MPC		0.91
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.75
gMVP		0.79

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: rs1191351549; hg19: chr5-79924919;