chr14-22589147-G-C

Position:

• chr14-22589147-G-C

Variant summary

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

The NM_001344.4(DAD1):​c.11C>G​(p.Ser4Trp) 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: 7.34

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.11C>G	p.Ser4Trp	missense_variant	1/3	ENST00000250498.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAD1	ENST00000250498.9	c.11C>G	p.Ser4Trp	missense_variant	1/3	1	NM_001344.4	P1
DAD1	ENST00000543337.1	c.11C>G	p.Ser4Trp	missense_variant	1/3	3
DAD1	ENST00000538631.1	c.11C>G	p.Ser4Trp	missense_variant	1/2	2
DAD1	ENST00000535847.1	c.11C>G	p.Ser4Trp	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

Jul 05, 2023

The c.11C>G (p.S4W) alteration is located in exon 1 (coding exon 1) of the DAD1 gene. This alteration results from a C to G substitution at nucleotide position 11, causing the serine (S) at amino acid position 4 to be replaced by a tryptophan (W). 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	Uncertain	0.51
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D;T;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Pathogenic	2.9	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.91	P;.;.
Vest4		0.59
MutPred		0.52		Gain of catalytic residue at A3 (P = 0);Gain of catalytic residue at A3 (P = 0);Gain of catalytic residue at A3 (P = 0);
MVP		0.60
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs757044016; hg19: chr14-23058053;