chr17-40344694-C-T

Variant names:

• chr17-40344694-C-T
• rs112509970
• NM_000964.4:c.179-3622C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000964.4(RARA):​c.179-3622C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00955 in 152,284 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.0096 (10 hom., cov: 32)
• Consequence: RARA NM_000964.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.126
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-40344694-C-T is Benign according to our data. Variant chr17-40344694-C-T is described in ClinVar as Benign. ClinVar VariationId is 2647736.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 1455 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARA	NM_000964.4	MANE Select	c.179-3622C>T		intron	N/A	NP_000955.1	P10276-1
	RARA	NM_001145301.3		c.179-3622C>T		intron	N/A	NP_001138773.1	Q6I9R7
	RARA	NM_001024809.4		c.163+1827C>T		intron	N/A	NP_001019980.1	P10276-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARA	ENST00000254066.10	TSL:1 MANE Select	c.179-3622C>T		intron	N/A	ENSP00000254066.5	P10276-1
	RARA	ENST00000394081.7	TSL:1	c.163+1827C>T		intron	N/A	ENSP00000377643.3	P10276-2
	RARA	ENST00000425707.7	TSL:1	c.179-7216C>T		intron	N/A	ENSP00000389993.3	P10276-3

Frequencies

GnomAD3 genomes AF: 0.00958 AC: 1458 AN: 152166 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.0115

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

GnomAD4 genome AF: 0.00955 AC: 1455 AN: 152284 Hom.: 10 Cov.: 32 AF XY: 0.00905 AC XY: 674 AN XY: 74462

African (AFR) AF: 0.00255 AC: 106 AN: 41562

American (AMR) AF: 0.00902 AC: 138 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 91 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4830

European-Finnish (FIN) AF: 0.0102 AC: 108 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0142 AC: 965 AN: 68014

Other (OTH) AF: 0.0114 AC: 24 AN: 2110

Alfa AF: 0.00498 Hom.: 0

Bravo AF: 0.00881

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.3
DANN	Benign	0.57
PhyloP100		-0.13
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: rs112509970; hg19: chr17-38500946;