Genetic Variant RAI14:p.Asp50Asn (chr5-34757579-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_015577.3(RAI14):c.148G>A(p.Asp50Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

RAI14
NM_015577.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

RAI14 (HGNC:14873): (retinoic acid induced 14) Predicted to enable actin binding activity. Predicted to be involved in several processes, including apoptotic signaling pathway; regulation of NIK/NF-kappaB signaling; and spermatogenesis. Located in cytosol; fibrillar center; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RAI14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
RAI14	NM_015577.3 link	c.148G>A	p.Asp50Asn	missense_variant	Exon 3 of 18	ENST00000265109.8	NP_056392.2	Q9P0K7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAI14	ENST00000265109.8 link	c.148G>A	p.Asp50Asn	missense_variant	Exon 3 of 18	1	NM_015577.3	ENSP00000265109.3		Q9P0K7-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250172

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1460778

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726534

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.157G>A (p.D53N) alteration is located in exon 5 (coding exon 2) of the RAI14 gene. This alteration results from a G to A substitution at nucleotide position 157, causing the aspartic acid (D) at amino acid position 53 to be replaced by an asparagine (N). 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

Benign

0.31

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;T;.;.;T;.;T;T;T;T;.;.;.;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

.;D;.;D;.;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.070

MetaRNN

Uncertain

0.48

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.12

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.2

D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.018

D;D;D;D;D;D;D;T;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.99

D;.;.;.;D;.;D;.;.;.;D;.;.;D

Vest4

0.81

MutPred

0.38

Loss of ubiquitination at K48 (P = 0.0273);Loss of ubiquitination at K48 (P = 0.0273);Loss of ubiquitination at K48 (P = 0.0273);Loss of ubiquitination at K48 (P = 0.0273);Loss of ubiquitination at K48 (P = 0.0273);Loss of ubiquitination at K48 (P = 0.0273);Loss of ubiquitination at K48 (P = 0.0273);Loss of ubiquitination at K48 (P = 0.0273);Loss of ubiquitination at K48 (P = 0.0273);Loss of ubiquitination at K48 (P = 0.0273);.;Loss of ubiquitination at K48 (P = 0.0273);Loss of ubiquitination at K48 (P = 0.0273);.;

MVP

0.81

MPC

0.67

ClinPred

0.92

GERP RS

5.7

Varity_R

0.24

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over