rs11742668

Variant names:

• chr5-80644085-T-C
• rs11742668
• NM_000791.4:c.242+5304A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000791.4(DHFR):​c.242+5304A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0754 in 152,286 control chromosomes in the GnomAD database, including 485 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.075 (485 hom., cov: 32)
• Consequence: DHFR NM_000791.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.308
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHFR	NM_000791.4	c.242+5304A>G		intron_variant	Intron 3 of 5	ENST00000439211.7	NP_000782.1
DHFR	NM_001290354.2	c.86+5304A>G		intron_variant	Intron 2 of 4		NP_001277283.1
DHFR	NM_001290357.2	c.242+5304A>G		intron_variant	Intron 3 of 4		NP_001277286.1
DHFR	NR_110936.2	n.686+5304A>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHFR	ENST00000439211.7	c.242+5304A>G		intron_variant	Intron 3 of 5	1	NM_000791.4	ENSP00000396308.2

Frequencies

GnomAD3 genomes AF: 0.0755 AC: 11489 AN: 152168 Hom.: 486 Cov.: 32

Gnomad AFR AF: 0.0511

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.0721

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.0169

Gnomad SAS AF: 0.0658

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0919

Gnomad OTH AF: 0.0670

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0754 AC: 11488 AN: 152286 Hom.: 485 Cov.: 32 AF XY: 0.0752 AC XY: 5596 AN XY: 74446

African (AFR) AF: 0.0511 AC: 2122 AN: 41562

American (AMR) AF: 0.0721 AC: 1103 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3472

East Asian (EAS) AF: 0.0168 AC: 87 AN: 5186

South Asian (SAS) AF: 0.0655 AC: 316 AN: 4828

European-Finnish (FIN) AF: 0.101 AC: 1076 AN: 10610

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0918 AC: 6247 AN: 68016

Other (OTH) AF: 0.0664 AC: 140 AN: 2110

Alfa AF: 0.0815 Hom.: 85

Bravo AF: 0.0710

Asia WGS AF: 0.0470 AC: 165 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.8
DANN	Benign	0.72
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs11742668; hg19: chr5-79939904;