rs12535

Variant names:

• chr2-158807104-G-A
• rs12535
• NM_001017920.3:c.196G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-158807104-G-A
• chr2-158807104-G-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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 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
• Publications: 19 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
DAPL1	NM_001017920.3	c.196G>A	p.Ala66Thr	missense_variant	Exon 3 of 4	ENST00000309950.8	NP_001017920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DAPL1	ENST00000309950.8	c.196G>A	p.Ala66Thr	missense_variant	Exon 3 of 4	1	NM_001017920.3	ENSP00000309538.4
DAPL1	ENST00000621326.4	c.196G>A	p.Ala66Thr	missense_variant	Exon 3 of 5	1		ENSP00000479872.1
DAPL1	ENST00000343761.4	c.121G>A	p.Ala41Thr	missense_variant	Exon 2 of 4	3		ENSP00000385306.2
DAPL1	ENST00000409042.5	c.196G>A	p.Ala66Thr	missense_variant	Exon 3 of 5	4		ENSP00000386422.1

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

GnomAD2 exomes AF: 0.225 AC: 56285 AN: 249660 AF XY: 0.230

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 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

African (AFR) AF: 0.0441 AC: 1470 AN: 33354

American (AMR) AF: 0.128 AC: 5676 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 6816 AN: 25988

East Asian (EAS) AF: 0.0148 AC: 587 AN: 39562

South Asian (SAS) AF: 0.141 AC: 12088 AN: 85498

European-Finnish (FIN) AF: 0.316 AC: 16842 AN: 53274

Middle Eastern (MID) AF: 0.252 AC: 1447 AN: 5734

European-Non Finnish (NFE) AF: 0.314 AC: 347883 AN: 1107676

Other (OTH) AF: 0.255 AC: 15282 AN: 60030

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

African (AFR) AF: 0.0548 AC: 2276 AN: 41516

American (AMR) AF: 0.174 AC: 2658 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 923 AN: 3470

East Asian (EAS) AF: 0.0263 AC: 136 AN: 5180

South Asian (SAS) AF: 0.129 AC: 620 AN: 4822

European-Finnish (FIN) AF: 0.320 AC: 3369 AN: 10534

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21729 AN: 67998

Other (OTH) AF: 0.232 AC: 489 AN: 2112

Alfa AF: 0.274 Hom.: 27004

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;.;.
PhyloP100		0.33
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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