NM_000964.4:c.*2C>T

Variant names:

• chr17-40356228-C-T
• rs2229773
• NM_000964.4:c.*2C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000964.4(RARA):​c.*2C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,549,578 control chromosomes in the GnomAD database, including 367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.015 (29 hom., cov: 33)
  • Exomes 𝑓: 0.021 (338 hom.)
• Consequence: RARA NM_000964.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.228

Genes affected

RARA (HGNC:9864): (retinoic acid receptor alpha) This gene represents a nuclear retinoic acid receptor. The encoded protein, retinoic acid receptor alpha, regulates transcription in a ligand-dependent manner. This gene has been implicated in regulation of development, differentiation, apoptosis, granulopoeisis, and transcription of clock genes. Translocations between this locus and several other loci have been associated with acute promyelocytic leukemia. Alternatively spliced transcript variants have been found for this locus.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0151 (2298/152282) while in subpopulation NFE AF= 0.0228 (1548/68002). AF 95% confidence interval is 0.0218. There are 29 homozygotes in gnomad4. There are 1139 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 2298 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARA	NM_000964.4	c.*2C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000254066.10	NP_000955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARA	ENST00000254066.10	c.*2C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_000964.4	ENSP00000254066.5

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2299 AN: 152164 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.00372

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0138 AC: 1994 AN: 144368 Hom.: 13 AF XY: 0.0134 AC XY: 1048 AN XY: 78100

Gnomad AFR exome AF: 0.00299

Gnomad AMR exome AF: 0.00798

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00478

Gnomad FIN exome AF: 0.0245

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0177

GnomAD4 exome AF: 0.0208 AC: 29011 AN: 1397296 Hom.: 338 Cov.: 35 AF XY: 0.0204 AC XY: 14069 AN XY: 689196

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.00883

Gnomad4 ASJ exome AF: 0.00588

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00567

Gnomad4 FIN exome AF: 0.0222

Gnomad4 NFE exome AF: 0.0239

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0151 AC: 2298 AN: 152282 Hom.: 29 Cov.: 33 AF XY: 0.0153 AC XY: 1139 AN XY: 74476

Gnomad4 AFR AF: 0.00371

Gnomad4 AMR AF: 0.0178

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00517

Gnomad4 FIN AF: 0.0230

Gnomad4 NFE AF: 0.0228

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0184 Hom.: 12

Bravo AF: 0.0138

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Meniere disease Uncertain:1

Jan 09, 2024

Meniere Disease Neuroscience Research Program, Faculty of Medicine and Health, Kolling Institute, The University of Sydney

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The NC_000017.11:g.40356228C>T, is a downstream variant in GJD3 gene. The variant is part of an haplotype involved in Meniere’s Disease, composed by g.40356228C>T, g.40363058C>G, g.40363293G>A, g.40363294C>G and g.40363579G>T. The haplotype was found in 10 individuals with familial Meniere’s Disease, segregating in 3 of these families (PP1); and in another 8 individuals with sporadic Meniere’s Disease. The position is not conserved (phyloP = 0.228) (BP4). In summary, this variant meets the criteria to be classified as uncertain significance based on the ACMG/AMP criteria applied: PP1, BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.1
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs2229773; hg19: chr17-38512480;