chr14-22589135-A-G

Position:

• chr14-22589135-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001344.4(DAD1):​c.23T>C​(p.Val8Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DAD1 NM_001344.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.70

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAD1	NM_001344.4	c.23T>C	p.Val8Ala	missense_variant	1/3	ENST00000250498.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAD1	ENST00000250498.9	c.23T>C	p.Val8Ala	missense_variant	1/3	1	NM_001344.4	P1
DAD1	ENST00000543337.1	c.23T>C	p.Val8Ala	missense_variant	1/3	3
DAD1	ENST00000538631.1	c.23T>C	p.Val8Ala	missense_variant	1/2	2
DAD1	ENST00000535847.1	c.23T>C	p.Val8Ala	missense_variant, NMD_transcript_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.23T>C (p.V8A) alteration is located in exon 1 (coding exon 1) of the DAD1 gene. This alteration results from a T to C substitution at nucleotide position 23, causing the valine (V) at amino acid position 8 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.28
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.0020	B;.;.
Vest4		0.77
MutPred		0.63		Gain of disorder (P = 0.0516);Gain of disorder (P = 0.0516);Gain of disorder (P = 0.0516);
MVP		0.54
MPC		0.74
ClinPred		0.94	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-23058041;