NM_000791.4:c.512A>G

Variant names:

• chr5-80629139-T-C
• rs1445173661
• NM_000791.4:c.512A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000791.4(DHFR):​c.512A>G​(p.Gln171Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q171Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DHFR NM_000791.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.36
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHFR	NM_000791.4	MANE Select	c.512A>G	p.Gln171Arg	missense	Exon 6 of 6	NP_000782.1	P00374-1
	DHFR	NM_001290354.2		c.356A>G	p.Gln119Arg	missense	Exon 5 of 5	NP_001277283.1	P00374-2
	DHFR	NM_001290357.2		c.*6A>G		3_prime_UTR	Exon 5 of 5	NP_001277286.1	B4DM58

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHFR	ENST00000439211.7	TSL:1 MANE Select	c.512A>G	p.Gln171Arg	missense	Exon 6 of 6	ENSP00000396308.2	P00374-1
	DHFR	ENST00000513048.5	TSL:1	n.393A>G		non_coding_transcript_exon	Exon 4 of 4
	DHFR	ENST00000505337.5	TSL:2	c.512A>G	p.Gln171Arg	missense	Exon 6 of 7	ENSP00000426474.1	P00374-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.03e-7 AC: 1 AN: 1422114 Hom.: 0 Cov.: 24 AF XY: 0.00000141 AC XY: 1 AN XY: 709536

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32506

American (AMR) AF: 0.00 AC: 0 AN: 43882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25722

East Asian (EAS) AF: 0.00 AC: 0 AN: 39378

South Asian (SAS) AF: 0.00 AC: 0 AN: 83436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079428

Other (OTH) AF: 0.00 AC: 0 AN: 59028

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.4
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.078	T
Polyphen		0.97	D
Vest4		0.49
MutPred		0.44		Gain of phosphorylation at S168 (P = 0.0827)
MVP		0.88
MPC		1.3
ClinPred		0.96	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.93
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs1445173661; hg19: chr5-79924958;