1-97573881-C-T

Variant names:

• chr1-97573881-C-T
• rs61622928
• NM_000110.4:c.1218G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000110.4(DPYD):​c.1218G>A​(p.Met406Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00393 in 1,613,662 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.020 (98 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (87 hom.)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4 O:1
• Conservation: PhyloP100: 3.71
• Publications: 27 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027598143).
• BP6: Variant 1-97573881-C-T is Benign according to our data. Variant chr1-97573881-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 100101.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0679 is higher than 0.05.

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.1218G>A	p.Met406Ile	missense	Exon 11 of 23	NP_000101.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	ENST00000370192.8	TSL:1 MANE Select	c.1218G>A	p.Met406Ile	missense	Exon 11 of 23	ENSP00000359211.3
	DPYD	ENST00000876340.1		c.1386G>A	p.Met462Ile	missense	Exon 12 of 24	ENSP00000546399.1
	DPYD	ENST00000969915.1		c.1218G>A	p.Met406Ile	missense	Exon 11 of 24	ENSP00000639974.1

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3080 AN: 152052 Hom.: 97 Cov.: 32

Gnomad AFR AF: 0.0696

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00879

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00501 AC: 1259 AN: 251118 AF XY: 0.00365

Gnomad AFR exome AF: 0.0655

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00221 AC: 3235 AN: 1461492 Hom.: 87 Cov.: 31 AF XY: 0.00194 AC XY: 1407 AN XY: 727044

African (AFR) AF: 0.0718 AC: 2403 AN: 33458

American (AMR) AF: 0.00418 AC: 187 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000766 AC: 20 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86248

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53410

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.000191 AC: 212 AN: 1111720

Other (OTH) AF: 0.00604 AC: 365 AN: 60384

GnomAD4 genome AF: 0.0204 AC: 3104 AN: 152170 Hom.: 98 Cov.: 32 AF XY: 0.0200 AC XY: 1491 AN XY: 74396

African (AFR) AF: 0.0700 AC: 2905 AN: 41510

American (AMR) AF: 0.00878 AC: 134 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68000

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.0101 Hom.: 131

Bravo AF: 0.0229

ESP6500AA AF: 0.0576 AC: 254

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00605 AC: 734

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	1	-	Dihydropyrimidine dehydrogenase deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.7
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.87	N
REVEL	Uncertain	0.33
Sift	Benign	0.46	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.41
MutPred		0.51		Loss of sheet (P = 0.0181)
MVP		0.88
MPC		0.060
ClinPred		0.011	T
GERP RS		5.8
Varity_R		0.51
gMVP		0.52
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61622928; hg19: chr1-98039437;