NM_000964.4:c.-363+4483A>G

Variant names:

• chr17-40313769-A-G
• rs7217852
• NM_000964.4:c.-363+4483A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000964.4(RARA):​c.-363+4483A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 151,864 control chromosomes in the GnomAD database, including 7,019 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 0.25 (7019 hom., cov: 31)
• Consequence: RARA NM_000964.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0860
• Publications: 8 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARA	NM_000964.4	MANE Select	c.-363+4483A>G		intron	N/A	NP_000955.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARA	ENST00000254066.10	TSL:1 MANE Select	c.-363+4483A>G		intron	N/A	ENSP00000254066.5
	RARA	ENST00000577646.5	TSL:5	c.-440+4483A>G		intron	N/A	ENSP00000464287.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37843 AN: 151746 Hom.: 6976 Cov.: 31

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0957

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.203

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

GnomAD4 genome AF: 0.250 AC: 37945 AN: 151864 Hom.: 7019 Cov.: 31 AF XY: 0.248 AC XY: 18443 AN XY: 74226

African (AFR) AF: 0.524 AC: 21647 AN: 41348

American (AMR) AF: 0.176 AC: 2694 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0957 AC: 332 AN: 3468

East Asian (EAS) AF: 0.352 AC: 1807 AN: 5138

South Asian (SAS) AF: 0.110 AC: 526 AN: 4800

European-Finnish (FIN) AF: 0.143 AC: 1512 AN: 10572

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8769 AN: 67942

Other (OTH) AF: 0.201 AC: 425 AN: 2110

Alfa AF: 0.232 Hom.: 1162

Bravo AF: 0.266

Asia WGS AF: 0.241 AC: 839 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.57
PhyloP100		0.086
Mutation Taster		=100/0	polymorphism (auto)

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: rs7217852; hg19: chr17-38470021;