Genetic Variant DAP:p.His79Asn (chr5-10681130-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004394.3(DAP):c.235C>A(p.His79Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. H79Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

DAP
NM_004394.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.37

Publications

0 publications found

Variant links:

Genes affected

DAP (HGNC:2672): (death associated protein) This gene encodes a basic, proline-rich, 15-kD protein. The protein acts as a positive mediator of programmed cell death that is induced by interferon-gamma. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

DAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAP	NM_004394.3 link	c.235C>A	p.His79Asn	missense_variant	Exon 4 of 4	ENST00000230895.11	NP_004385.1	P51397
DAP	NM_001291963.2 link	c.192C>A	p.Leu64Leu	synonymous_variant	Exon 3 of 3		NP_001278892.1	P51397B4DQ75

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DAP	ENST00000230895.11 link	c.235C>A	p.His79Asn	missense_variant	Exon 4 of 4	1	NM_004394.3	ENSP00000230895.7	P51397
DAP	ENST00000432074.2 link	c.192C>A	p.Leu64Leu	synonymous_variant	Exon 3 of 3	2		ENSP00000394163.2	B4DQ75
DAP	ENST00000514882.5 link	n.523C>A		non_coding_transcript_exon_variant	Exon 4 of 4	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1397230

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688258

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31350

American (AMR)

AF:

0.00

AC:

AN:

34046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22452

East Asian (EAS)

AF:

0.00

AC:

AN:

38850

South Asian (SAS)

AF:

0.00

AC:

AN:

74704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5482

European-Non Finnish (NFE)

AF:

9.24e-7

AC:

AN:

1082204

Other (OTH)

AF:

0.00

AC:

AN:

57448

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.3

PhyloP100

7.4

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.85

MutPred

0.45

Gain of ubiquitination at K81 (P = 0.0918);

MVP

0.94

MPC

0.77

ClinPred

0.99

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.73

Mutation Taster

=90/10

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over