chr17-40349934-C-T

Variant names:

• chr17-40349934-C-T
• rs139421379
• NM_000964.4:c.469+9C>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.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
• 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

ENSG00000278918 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 771766.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 554 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.469+9C>T		intron	N/A	NP_000955.1	P10276-1
	RARA	NM_001145301.3		c.469+9C>T		intron	N/A	NP_001138773.1	Q6I9R7
	RARA	NM_001024809.4		c.454+9C>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.469+9C>T		intron	N/A	ENSP00000254066.5	P10276-1
	RARA	ENST00000394081.7	TSL:1	c.454+9C>T		intron	N/A	ENSP00000377643.3	P10276-2
	RARA	ENST00000425707.7	TSL:1	c.179-1976C>T		intron	N/A	ENSP00000389993.3	P10276-3

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

GnomAD2 exomes AF: 0.00333 AC: 834 AN: 250440 AF XY: 0.00335

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 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

African (AFR) AF: 0.00134 AC: 45 AN: 33474

American (AMR) AF: 0.00226 AC: 101 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86234

European-Finnish (FIN) AF: 0.000843 AC: 45 AN: 53406

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00806 AC: 8964 AN: 1111598

Other (OTH) AF: 0.00485 AC: 293 AN: 60376

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

African (AFR) AF: 0.00161 AC: 67 AN: 41576

American (AMR) AF: 0.00346 AC: 53 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00603 AC: 410 AN: 68038

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00432 Hom.: 1

Bravo AF: 0.00371

Asia WGS AF: 0.000289 AC: 1 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	-0.81
CADD	Benign	6.8
DANN	Benign	0.67
PhyloP100		0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs139421379; hg19: chr17-38506186;