17-40323579-C-T

Variant names:

• chr17-40323579-C-T
• rs9904270
• NM_000964.4:c.-362-7278C>T

Variant summary

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

The NM_000964.4(RARA):​c.-362-7278C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 151,742 control chromosomes in the GnomAD database, including 1,233 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 0.12 (1233 hom., cov: 30)
• Consequence: RARA NM_000964.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0290
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARA	NM_000964.4	c.-362-7278C>T		intron_variant	Intron 1 of 8	ENST00000254066.10	NP_000955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARA	ENST00000254066.10	c.-362-7278C>T		intron_variant	Intron 1 of 8	1	NM_000964.4	ENSP00000254066.5

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17641 AN: 151624 Hom.: 1225 Cov.: 30

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0897

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.0987

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0908

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

GnomAD4 genome AF: 0.116 AC: 17667 AN: 151742 Hom.: 1233 Cov.: 30 AF XY: 0.118 AC XY: 8730 AN XY: 74120

African (AFR) AF: 0.110 AC: 4528 AN: 41326

American (AMR) AF: 0.118 AC: 1793 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0897 AC: 311 AN: 3466

East Asian (EAS) AF: 0.359 AC: 1839 AN: 5126

South Asian (SAS) AF: 0.0996 AC: 478 AN: 4798

European-Finnish (FIN) AF: 0.120 AC: 1271 AN: 10558

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7042 AN: 67912

Other (OTH) AF: 0.0913 AC: 192 AN: 2104

Alfa AF: 0.109 Hom.: 1038

Bravo AF: 0.118

Asia WGS AF: 0.204 AC: 707 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.5
DANN	Benign	0.43
PhyloP100		-0.029
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: rs9904270; hg19: chr17-38479831; COSMIC: COSV54190598;