5-34813625-C-T

Variant names:

• chr5-34813625-C-T
• rs1380064059
• NM_015577.3:c.817C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015577.3(RAI14):​c.817C>T​(p.Arg273Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RAI14 NM_015577.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25
• Publications: 5 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35365587).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015577.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAI14	NM_015577.3	MANE Select	c.817C>T	p.Arg273Cys	missense	Exon 11 of 18	NP_056392.2	Q9P0K7-1
	RAI14	NM_001145525.2		c.826C>T	p.Arg276Cys	missense	Exon 13 of 20	NP_001138997.1	Q9P0K7-2
	RAI14	NM_001145520.1		c.817C>T	p.Arg273Cys	missense	Exon 11 of 18	NP_001138992.1	Q9P0K7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAI14	ENST00000265109.8	TSL:1 MANE Select	c.817C>T	p.Arg273Cys	missense	Exon 11 of 18	ENSP00000265109.3	Q9P0K7-1
	RAI14	ENST00000515799.5	TSL:1	c.826C>T	p.Arg276Cys	missense	Exon 13 of 20	ENSP00000427123.1	Q9P0K7-2
	RAI14	ENST00000428746.6	TSL:1	c.817C>T	p.Arg273Cys	missense	Exon 11 of 18	ENSP00000388725.2	Q9P0K7-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461188 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726928

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111580

Other (OTH) AF: 0.0000166 AC: 1 AN: 60356

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.36		Loss of MoRF binding (P = 0.0235)
MVP		0.49
MPC		0.79
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.24
gMVP		0.48
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1380064059; hg19: chr5-34813730; COSMIC: COSV54289207; COSMIC: COSV54289207;