14-22575361-A-G

Position:

• chr14-22575361-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001344.4(DAD1):​c.212-128T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,028,132 control chromosomes in the GnomAD database, including 2,515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (1190 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1325 hom.)
• Consequence: DAD1 NM_001344.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0910

Genes affected

DAD1 (HGNC:2664): (defender against cell death 1) DAD1, the defender against apoptotic cell death, was initially identified as a negative regulator of programmed cell death in the temperature sensitive tsBN7 cell line. The DAD1 protein disappeared in temperature-sensitive cells following a shift to the nonpermissive temperature, suggesting that loss of the DAD1 protein triggered apoptosis. DAD1 is believed to be a tightly associated subunit of oligosaccharyltransferase both in the intact membrane and in the purified enzyme, thus reflecting the essential nature of N-linked glycosylation in eukaryotes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-22575361-A-G is Benign according to our data. Variant chr14-22575361-A-G is described in ClinVar as [Benign]. Clinvar id is 1235041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAD1	NM_001344.4	c.212-128T>C		intron_variant		ENST00000250498.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAD1	ENST00000250498.9	c.212-128T>C		intron_variant		1	NM_001344.4	P1
DAD1	ENST00000538631.1	c.212-10224T>C		intron_variant		2
DAD1	ENST00000543337.1	c.128-128T>C		intron_variant		3
DAD1	ENST00000535847.1	c.123-128T>C		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0919 AC: 13977 AN: 152132 Hom.: 1187 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0530

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0385

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0889

GnomAD4 exome AF: 0.0449 AC: 39324 AN: 875882 Hom.: 1325 AF XY: 0.0440 AC XY: 19297 AN XY: 438882

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.0411

Gnomad4 ASJ exome AF: 0.0496

Gnomad4 EAS exome AF: 0.0000616

Gnomad4 SAS exome AF: 0.0223

Gnomad4 FIN exome AF: 0.0401

Gnomad4 NFE exome AF: 0.0429

Gnomad4 OTH exome AF: 0.0517

GnomAD4 genome AF: 0.0920 AC: 14009 AN: 152250 Hom.: 1190 Cov.: 32 AF XY: 0.0896 AC XY: 6673 AN XY: 74456

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.0529

Gnomad4 ASJ AF: 0.0513

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0226

Gnomad4 FIN AF: 0.0385

Gnomad4 NFE AF: 0.0448

Gnomad4 OTH AF: 0.0875

Alfa AF: 0.0553 Hom.: 335

Bravo AF: 0.0978

Asia WGS AF: 0.0250 AC: 90 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.8
DANN	Benign	0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs5742794; hg19: chr14-23044261;