17-40354331-C-T

Variant names:

• chr17-40354331-C-T
• rs77633370
• NM_000964.4:c.837C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000964.4(RARA):​c.837C>T​(p.Pro279Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00467 in 1,614,144 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (41 hom.)
• Consequence: RARA NM_000964.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.33
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 17-40354331-C-T is Benign according to our data. Variant chr17-40354331-C-T is described in ClinVar as Benign. ClinVar VariationId is 780426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1707/152264) while in subpopulation AFR AF = 0.0321 (1335/41542). AF 95% confidence interval is 0.0307. There are 18 homozygotes in GnomAd4. There are 837 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1707 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.837C>T	p.Pro279Pro	synonymous	Exon 7 of 9	NP_000955.1	P10276-1
	RARA	NM_001145301.3		c.837C>T	p.Pro279Pro	synonymous	Exon 7 of 9	NP_001138773.1	Q6I9R7
	RARA	NM_001024809.4		c.822C>T	p.Pro274Pro	synonymous	Exon 6 of 8	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.837C>T	p.Pro279Pro	synonymous	Exon 7 of 9	ENSP00000254066.5	P10276-1
	RARA	ENST00000394081.7	TSL:1	c.822C>T	p.Pro274Pro	synonymous	Exon 6 of 8	ENSP00000377643.3	P10276-2
	RARA	ENST00000425707.7	TSL:1	c.546C>T	p.Pro182Pro	synonymous	Exon 5 of 7	ENSP00000389993.3	P10276-3

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1696 AN: 152146 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0320

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00457 AC: 1148 AN: 251250 AF XY: 0.00396

Gnomad AFR exome AF: 0.0343

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00399

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00399 AC: 5833 AN: 1461880 Hom.: 41 Cov.: 33 AF XY: 0.00380 AC XY: 2762 AN XY: 727238

African (AFR) AF: 0.0320 AC: 1071 AN: 33478

American (AMR) AF: 0.00210 AC: 94 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 54 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000858 AC: 74 AN: 86256

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53412

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.00377 AC: 4195 AN: 1112012

Other (OTH) AF: 0.00518 AC: 313 AN: 60394

GnomAD4 genome AF: 0.0112 AC: 1707 AN: 152264 Hom.: 18 Cov.: 32 AF XY: 0.0112 AC XY: 837 AN XY: 74462

African (AFR) AF: 0.0321 AC: 1335 AN: 41542

American (AMR) AF: 0.00503 AC: 77 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00354 AC: 241 AN: 68006

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00686 Hom.: 9

Bravo AF: 0.0128

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00415

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.77
PhyloP100		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	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: rs77633370; hg19: chr17-38510583;