X-17800994-T-G

Position:

• chrX-17800994-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021785.6(RAI2):​c.1017A>C​(p.Glu339Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RAI2 NM_021785.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00100

Genes affected

RAI2 (HGNC:9835): (retinoic acid induced 2) Retinoic acid plays a critical role in development, cellular growth, and differentiation. The specific function of this retinoic acid-induced gene has not yet been determined but it may play a role in development. The chromosomal location of this gene designates it to be a candidate for diseases such as Nance-Horan syndrome, sensorineural deafness, non-specific X-linked cognitive disability, oral-facial-digital syndrome, and Fried syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0605613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAI2	NM_021785.6	c.1017A>C	p.Glu339Asp	missense_variant	2/2	ENST00000451717.6	NP_068557.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAI2	ENST00000451717.6	c.1017A>C	p.Glu339Asp	missense_variant	2/2	1	NM_021785.6	ENSP00000401323	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

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

Mar 18, 2024

The c.1017A>C (p.E339D) alteration is located in exon 3 (coding exon 1) of the RAI2 gene. This alteration results from a A to C substitution at nucleotide position 1017, causing the glutamic acid (E) at amino acid position 339 to be replaced by an aspartic acid (D). 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	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	.;T;T;T;T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.65	T;.;.;.;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.061	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;L;L;L;L
MutationTaster	Benign	0.87	D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.32	N;N;N;N;N
REVEL	Benign	0.027
Sift	Benign	0.25	T;T;T;T;T
Sift4G	Benign	0.36	T;T;T;T;T
Polyphen		0.012	.;B;B;B;B
Vest4		0.13
MutPred		0.20		.;Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);
MVP		0.29
MPC		0.12
ClinPred		0.12	T
GERP RS		1.1
Varity_R		0.076
gMVP		0.073

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: chrX-17819114;