rs56038477

Variant names:

• chr1-97573863-C-T
• rs56038477
• NM_000110.4:c.1236G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-97573863-C-T
• chr1-97573863-C-A
• chr1-97573863-C-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP7 BS1_Supporting BS2

The NM_000110.4(DPYD):​c.1236G>A​(p.Glu412Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,613,680 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 32)
  • Exomes 𝑓: 0.019 (335 hom.)
• Consequence: DPYD NM_000110.4 synonymous
• Clinical Significance: drug response reviewed by expert panel B:5 O:3
• Conservation: PhyloP100: 0.403
• Publications: 193 publications found

Genes affected

DPYD (HGNC:3012): (dihydropyrimidine dehydrogenase) The protein encoded by this gene is a pyrimidine catabolic enzyme and the initial and rate-limiting factor in the pathway of uracil and thymidine catabolism. Mutations in this gene result in dihydropyrimidine dehydrogenase deficiency, an error in pyrimidine metabolism associated with thymine-uraciluria and an increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

DPYD Gene-Disease associations (from GenCC):

• dihydropyrimidine dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP7: Synonymous conserved (PhyloP=0.403 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0131 (1993/152190) while in subpopulation NFE AF = 0.0214 (1455/68002). AF 95% confidence interval is 0.0205. There are 23 homozygotes in GnomAd4. There are 935 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000110.4. 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
	DPYD	NM_000110.4	MANE Select	c.1236G>A	p.Glu412Glu	synonymous	Exon 11 of 23	NP_000101.2	Q12882-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	ENST00000370192.8	TSL:1 MANE Select	c.1236G>A	p.Glu412Glu	synonymous	Exon 11 of 23	ENSP00000359211.3	Q12882-1
	DPYD	ENST00000876340.1		c.1404G>A	p.Glu468Glu	synonymous	Exon 12 of 24	ENSP00000546399.1
	DPYD	ENST00000969915.1		c.1236G>A	p.Glu412Glu	synonymous	Exon 11 of 24	ENSP00000639974.1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1994 AN: 152072 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00728

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0141 AC: 3543 AN: 251150 AF XY: 0.0151

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0211

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0194 AC: 28307 AN: 1461490 Hom.: 335 Cov.: 31 AF XY: 0.0194 AC XY: 14130 AN XY: 727058

African (AFR) AF: 0.00278 AC: 93 AN: 33460

American (AMR) AF: 0.00483 AC: 216 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00586 AC: 153 AN: 26120

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39682

South Asian (SAS) AF: 0.0173 AC: 1496 AN: 86246

European-Finnish (FIN) AF: 0.0133 AC: 709 AN: 53414

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5766

European-Non Finnish (NFE) AF: 0.0221 AC: 24593 AN: 1111708

Other (OTH) AF: 0.0161 AC: 972 AN: 60382

GnomAD4 genome AF: 0.0131 AC: 1993 AN: 152190 Hom.: 23 Cov.: 32 AF XY: 0.0126 AC XY: 935 AN XY: 74412

African (AFR) AF: 0.00294 AC: 122 AN: 41520

American (AMR) AF: 0.00727 AC: 111 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.0161 AC: 78 AN: 4830

European-Finnish (FIN) AF: 0.0142 AC: 151 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0214 AC: 1455 AN: 68002

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0181 Hom.: 69

Bravo AF: 0.0120

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0183

EpiControl AF: 0.0191

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	2	not specified (2)
-	-	1	Dihydropyrimidine dehydrogenase deficiency (1)
-	-	-	capecitabine response - Toxicity (1)
-	-	-	fluorouracil response - Toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	6.8
DANN	Benign	0.54
PhyloP100		0.40
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: rs56038477; hg19: chr1-98039419;