17-40340068-G-A

Variant names:

• chr17-40340068-G-A
• rs2715553
• NM_000964.4:c.179-8248G>A

Variant summary

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

The NM_000964.4(RARA):​c.179-8248G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 151,968 control chromosomes in the GnomAD database, including 31,038 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 0.62 (31038 hom., cov: 31)
• Consequence: RARA NM_000964.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0850
• Publications: 27 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.852 is higher than 0.05.

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.179-8248G>A		intron	N/A	NP_000955.1
	RARA	NM_001145301.3		c.179-8248G>A		intron	N/A	NP_001138773.1
	RARA	NM_001145302.3		c.178+8672G>A		intron	N/A	NP_001138774.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARA	ENST00000254066.10	TSL:1 MANE Select	c.179-8248G>A		intron	N/A	ENSP00000254066.5
	RARA	ENST00000425707.7	TSL:1	c.178+8672G>A		intron	N/A	ENSP00000389993.3
	RARA	ENST00000394089.6	TSL:2	c.179-8248G>A		intron	N/A	ENSP00000377649.2

Frequencies

GnomAD3 genomes AF: 0.619 AC: 94046 AN: 151850 Hom.: 30967 Cov.: 31

Gnomad AFR AF: 0.859

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.547

Gnomad OTH AF: 0.579

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

GnomAD4 genome AF: 0.620 AC: 94172 AN: 151968 Hom.: 31038 Cov.: 31 AF XY: 0.611 AC XY: 45375 AN XY: 74242

African (AFR) AF: 0.859 AC: 35650 AN: 41498

American (AMR) AF: 0.460 AC: 7016 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1953 AN: 3468

East Asian (EAS) AF: 0.522 AC: 2689 AN: 5154

South Asian (SAS) AF: 0.405 AC: 1950 AN: 4814

European-Finnish (FIN) AF: 0.546 AC: 5747 AN: 10526

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.547 AC: 37150 AN: 67934

Other (OTH) AF: 0.582 AC: 1225 AN: 2106

Alfa AF: 0.568 Hom.: 73442

Bravo AF: 0.625

Asia WGS AF: 0.529 AC: 1840 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	6.0
DANN	Benign	0.60
PhyloP100		-0.085
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: rs2715553; hg19: chr17-38496320;