chr17-40344662-T-C

Variant names:

• chr17-40344662-T-C
• rs9303285
• NM_000964.4:c.179-3654T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000964.4(RARA):​c.179-3654T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 152,150 control chromosomes in the GnomAD database, including 6,966 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (6966 hom., cov: 32)
• Consequence: RARA NM_000964.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.248
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARA	NM_000964.4	c.179-3654T>C		intron_variant	Intron 2 of 8	ENST00000254066.10	NP_000955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARA	ENST00000254066.10	c.179-3654T>C		intron_variant	Intron 2 of 8	1	NM_000964.4	ENSP00000254066.5

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37906 AN: 152032 Hom.: 6925 Cov.: 32

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.204

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.250 AC: 38007 AN: 152150 Hom.: 6966 Cov.: 32 AF XY: 0.249 AC XY: 18525 AN XY: 74370

African (AFR) AF: 0.519 AC: 21524 AN: 41488

American (AMR) AF: 0.176 AC: 2694 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3470

East Asian (EAS) AF: 0.371 AC: 1915 AN: 5166

South Asian (SAS) AF: 0.108 AC: 519 AN: 4826

European-Finnish (FIN) AF: 0.151 AC: 1604 AN: 10592

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8747 AN: 67990

Other (OTH) AF: 0.203 AC: 428 AN: 2108

Alfa AF: 0.174 Hom.: 834

Bravo AF: 0.265

Asia WGS AF: 0.240 AC: 835 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.5
DANN	Benign	0.74
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs9303285; hg19: chr17-38500914; COSMIC: COSV54190055;