NM_000964.4:c.826C>T

Variant names:

• chr17-40354320-C-T
• rs786205678
• NM_000964.4:c.826C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000964.4(RARA):​c.826C>T​(p.Arg276Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance,drug response (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R276Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RARA NM_000964.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 O:1
• Conservation: PhyloP100: -0.609
• Publications: 9 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-40354321-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 985591.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

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.826C>T	p.Arg276Trp	missense	Exon 7 of 9	NP_000955.1	P10276-1
	RARA	NM_001145301.3		c.826C>T	p.Arg276Trp	missense	Exon 7 of 9	NP_001138773.1	Q6I9R7
	RARA	NM_001024809.4		c.811C>T	p.Arg271Trp	missense	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.826C>T	p.Arg276Trp	missense	Exon 7 of 9	ENSP00000254066.5	P10276-1
	RARA	ENST00000394081.7	TSL:1	c.811C>T	p.Arg271Trp	missense	Exon 6 of 8	ENSP00000377643.3	P10276-2
	RARA	ENST00000425707.7	TSL:1	c.535C>T	p.Arg179Trp	missense	Exon 5 of 7	ENSP00000389993.3	P10276-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Syndromic disease (1)
-	-	-	Tretinoin response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Benign	0.94
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	0.063
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.42	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		-0.61
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.89		Gain of catalytic residue at P279 (P = 0.0232)
MVP		0.99
MPC		2.1
ClinPred		0.99	D
GERP RS		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.98
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs786205678; hg19: chr17-38510572; COSMIC: COSV54190879; COSMIC: COSV54190879;