chr5-80649321-T-C

Variant names:

• chr5-80649321-T-C
• rs10072026
• NM_000791.4:c.242+68A>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+68A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,118,484 control chromosomes in the GnomAD database, including 12,071 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 0.20 (4947 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7124 hom.)
• Consequence: DHFR NM_000791.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.575
• Publications: 23 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=-0.75).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHFR	NM_000791.4	MANE Select	c.242+68A>G		intron	N/A	NP_000782.1
	DHFR	NM_001290354.2		c.86+68A>G		intron	N/A	NP_001277283.1
	DHFR	NM_001290357.2		c.242+68A>G		intron	N/A	NP_001277286.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHFR	ENST00000439211.7	TSL:1 MANE Select	c.242+68A>G		intron	N/A	ENSP00000396308.2
	DHFR	ENST00000513048.5	TSL:1	n.250+68A>G		intron	N/A
	DHFR	ENST00000505337.5	TSL:2	c.242+68A>G		intron	N/A	ENSP00000426474.1

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30079 AN: 152048 Hom.: 4932 Cov.: 32

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.0179

Gnomad SAS AF: 0.0897

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.105 AC: 101330 AN: 966318 Hom.: 7124 Cov.: 12 AF XY: 0.103 AC XY: 49690 AN XY: 480468

African (AFR) AF: 0.470 AC: 10160 AN: 21640

American (AMR) AF: 0.110 AC: 2221 AN: 20264

Ashkenazi Jewish (ASJ) AF: 0.0610 AC: 1039 AN: 17030

East Asian (EAS) AF: 0.0401 AC: 1351 AN: 33728

South Asian (SAS) AF: 0.0877 AC: 3706 AN: 42256

European-Finnish (FIN) AF: 0.112 AC: 4988 AN: 44728

Middle Eastern (MID) AF: 0.104 AC: 297 AN: 2850

European-Non Finnish (NFE) AF: 0.0983 AC: 73041 AN: 742944

Other (OTH) AF: 0.111 AC: 4527 AN: 40878

GnomAD4 genome AF: 0.198 AC: 30140 AN: 152166 Hom.: 4947 Cov.: 32 AF XY: 0.193 AC XY: 14373 AN XY: 74410

African (AFR) AF: 0.454 AC: 18830 AN: 41458

American (AMR) AF: 0.125 AC: 1911 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3472

East Asian (EAS) AF: 0.0178 AC: 92 AN: 5180

South Asian (SAS) AF: 0.0888 AC: 428 AN: 4822

European-Finnish (FIN) AF: 0.114 AC: 1209 AN: 10602

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6847 AN: 68020

Other (OTH) AF: 0.176 AC: 371 AN: 2112

Alfa AF: 0.131 Hom.: 7161

Bravo AF: 0.211

Asia WGS AF: 0.0910 AC: 318 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	10
DANN	Benign	0.90
PhyloP100		-0.57
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: rs10072026; hg19: chr5-79945140;