rs12535

chr2-158807104-G-Achr2-158807104-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001017920.3(DAPL1):c.196G>A(p.Ala66Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,607,762 control chromosomes in the GnomAD database, including 66,920 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A66E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.21 (4600 hom., cov: 32)
  • Exomes 𝑓: 0.28 (62320 hom.)
• Consequence: DAPL1 NM_001017920.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.331

Genes affected

DAPL1 (HGNC:21490): (death associated protein like 1) Predicted to enable death domain binding activity. Predicted to be involved in apoptotic signaling pathway; cellular response to amino acid starvation; and negative regulation of autophagy. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004966527).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAPL1	NM_001017920.3	c.196G>A	p.Ala66Thr	missense_variant	3/4	ENST00000309950.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAPL1	ENST00000309950.8	c.196G>A	p.Ala66Thr	missense_variant	3/4	1	NM_001017920.3	P1
DAPL1	ENST00000621326.4	c.196G>A	p.Ala66Thr	missense_variant	3/5	1
DAPL1	ENST00000343761.4	c.124G>A	p.Ala42Thr	missense_variant	2/4	3
DAPL1	ENST00000409042.5	c.196G>A	p.Ala66Thr	missense_variant	3/5	4

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32688 AN: 152012 Hom.: 4600 Cov.: 32

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.0264

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.232

GnomAD3 exomes AF: 0.225 AC: 56285 AN: 249660 Hom.: 7948 AF XY: 0.230 AC XY: 31096 AN XY: 134992

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.0214

Gnomad SAS exome AF: 0.136

Gnomad FIN exome AF: 0.326

Gnomad NFE exome AF: 0.316

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.280 AC: 408091 AN: 1455632 Hom.: 62320 Cov.: 33 AF XY: 0.278 AC XY: 201371 AN XY: 724230

Gnomad4 AFR exome AF: 0.0441

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.0148

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.316

Gnomad4 NFE exome AF: 0.314

Gnomad4 OTH exome AF: 0.255

GnomAD4 genome AF: 0.215 AC: 32680 AN: 152130 Hom.: 4600 Cov.: 32 AF XY: 0.212 AC XY: 15749 AN XY: 74352

Gnomad4 AFR AF: 0.0548

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.0263

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.320

Gnomad4 NFE AF: 0.320

Gnomad4 OTH AF: 0.232

Alfa AF: 0.283 Hom.: 13401

Bravo AF: 0.195

TwinsUK AF: 0.305 AC: 1132

ALSPAC AF: 0.307 AC: 1182

ESP6500AA AF: 0.0581 AC: 256

ESP6500EA AF: 0.303 AC: 2604

ExAC AF: 0.227 AC: 27541

Asia WGS AF: 0.0940 AC: 325 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	1.9
Dann	Benign	0.61
DEOGEN2	Benign	0.011	T;.;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.49	T;T;T
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.86	N;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.11	N;.;N
REVEL	Benign	0.033
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.070
MPC		0.012
ClinPred		0.00034	T
GERP RS		1.9
Varity_R		0.029
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12535; hg19: chr2-159663616; COSMIC: COSV59353653;