17-40351852-G-T

Variant names:

• chr17-40351852-G-T
• rs4890109
• NM_000964.4:c.470-58G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000964.4(RARA):​c.470-58G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,571,084 control chromosomes in the GnomAD database, including 1,414 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 0.028 (101 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1313 hom.)
• Consequence: RARA NM_000964.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.199
• Publications: 13 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=-0.77).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0282 (4300/152254) while in subpopulation NFE AF = 0.0449 (3055/67988). AF 95% confidence interval is 0.0436. There are 101 homozygotes in GnomAd4. There are 2077 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4300 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARA	NM_000964.4	c.470-58G>T		intron_variant	Intron 4 of 8	ENST00000254066.10	NP_000955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARA	ENST00000254066.10	c.470-58G>T		intron_variant	Intron 4 of 8	1	NM_000964.4	ENSP00000254066.5

Frequencies

GnomAD3 genomes AF: 0.0283 AC: 4304 AN: 152136 Hom.: 101 Cov.: 32

Gnomad AFR AF: 0.00707

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0182

GnomAD4 exome AF: 0.0403 AC: 57111 AN: 1418830 Hom.: 1313 AF XY: 0.0399 AC XY: 28124 AN XY: 705554

African (AFR) AF: 0.00591 AC: 182 AN: 30806

American (AMR) AF: 0.0105 AC: 337 AN: 32018

Ashkenazi Jewish (ASJ) AF: 0.0384 AC: 934 AN: 24294

East Asian (EAS) AF: 0.000154 AC: 6 AN: 39020

South Asian (SAS) AF: 0.0245 AC: 1953 AN: 79812

European-Finnish (FIN) AF: 0.0436 AC: 2237 AN: 51324

Middle Eastern (MID) AF: 0.0119 AC: 57 AN: 4806

European-Non Finnish (NFE) AF: 0.0447 AC: 49084 AN: 1098198

Other (OTH) AF: 0.0396 AC: 2321 AN: 58552

GnomAD4 genome AF: 0.0282 AC: 4300 AN: 152254 Hom.: 101 Cov.: 32 AF XY: 0.0279 AC XY: 2077 AN XY: 74436

African (AFR) AF: 0.00705 AC: 293 AN: 41574

American (AMR) AF: 0.0120 AC: 184 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 157 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.0213 AC: 103 AN: 4826

European-Finnish (FIN) AF: 0.0439 AC: 466 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0449 AC: 3055 AN: 67988

Other (OTH) AF: 0.0180 AC: 38 AN: 2108

Alfa AF: 0.0347 Hom.: 65

Bravo AF: 0.0243

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		0.20
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: rs4890109; hg19: chr17-38508104; COSMIC: COSV54189999;