rs2229773

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate 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
• Publications: 12 publications found

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]

RARA Gene-Disease associations (from GenCC):

• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• acute promyelocytic leukemia

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.05).
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 2298 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000964.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARA	NM_000964.4	MANE Select	c.*2C>T		3_prime_UTR	Exon 9 of 9	NP_000955.1
	RARA	NM_001145301.3		c.*2C>T		3_prime_UTR	Exon 9 of 9	NP_001138773.1
	RARA	NM_001024809.4		c.*2C>T		3_prime_UTR	Exon 8 of 8	NP_001019980.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARA	ENST00000254066.10	TSL:1 MANE Select	c.*2C>T		3_prime_UTR	Exon 9 of 9	ENSP00000254066.5
	RARA	ENST00000394081.7	TSL:1	c.*2C>T		3_prime_UTR	Exon 8 of 8	ENSP00000377643.3
	RARA	ENST00000425707.7	TSL:1	c.*2C>T		3_prime_UTR	Exon 7 of 7	ENSP00000389993.3

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

GnomAD2 exomes AF: 0.0138 AC: 1994 AN: 144368 AF XY: 0.0134

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 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

African (AFR) AF: 0.00320 AC: 101 AN: 31600

American (AMR) AF: 0.00883 AC: 315 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.00588 AC: 148 AN: 25164

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35728

South Asian (SAS) AF: 0.00567 AC: 449 AN: 79226

European-Finnish (FIN) AF: 0.0222 AC: 1055 AN: 47606

Middle Eastern (MID) AF: 0.0133 AC: 76 AN: 5698

European-Non Finnish (NFE) AF: 0.0239 AC: 25806 AN: 1078616

Other (OTH) AF: 0.0183 AC: 1060 AN: 57968

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

African (AFR) AF: 0.00371 AC: 154 AN: 41558

American (AMR) AF: 0.0178 AC: 273 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00517 AC: 25 AN: 4832

European-Finnish (FIN) AF: 0.0230 AC: 244 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0228 AC: 1548 AN: 68002

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.0184 Hom.: 12

Bravo AF: 0.0138

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Meniere disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.1
DANN	Benign	0.88
PhyloP100		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2229773; hg19: chr17-38512480;