17-40349934-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000964.4(RARA):c.469+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00621 in 1,613,688 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (43 hom.)
• Consequence: RARA NM_000964.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.418

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-40349934-C-T is Benign according to our data. Variant chr17-40349934-C-T is described in ClinVar as [Benign]. Clinvar id is 771766.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 554 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARA	NM_000964.4	c.469+9C>T		intron_variant		ENST00000254066.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARA	ENST00000254066.10	c.469+9C>T		intron_variant		1	NM_000964.4	P4
	ENST00000623156.1	n.606G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00364 AC: 554 AN: 152236 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00603

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00333 AC: 834 AN: 250440 Hom.: 3 AF XY: 0.00335 AC XY: 454 AN XY: 135370

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000926

Gnomad NFE exome AF: 0.00607

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00648 AC: 9473 AN: 1461334 Hom.: 43 Cov.: 31 AF XY: 0.00627 AC XY: 4555 AN XY: 726978

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.000843

Gnomad4 NFE exome AF: 0.00806

Gnomad4 OTH exome AF: 0.00485

GnomAD4 genome AF: 0.00364 AC: 554 AN: 152354 Hom.: 1 Cov.: 32 AF XY: 0.00350 AC XY: 261 AN XY: 74516

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00603

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00432 Hom.: 1

Bravo AF: 0.00371

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	6.8
Dann	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139421379; hg19: chr17-38506186;