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GeneBe

17-40354331-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_000964.4(RARA):c.837C>T(p.Pro279=) 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

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.33
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-40354331-C-T is Benign according to our data. Variant chr17-40354331-C-T is described in ClinVar as [Benign]. Clinvar id is 780426.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-3.33 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 1696 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RARANM_000964.4 linkuse as main transcriptc.837C>T p.Pro279= synonymous_variant 7/9 ENST00000254066.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RARAENST00000254066.10 linkuse as main transcriptc.837C>T p.Pro279= synonymous_variant 7/91 NM_000964.4 P4P10276-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0111
AC:
1696
AN:
152146
Hom.:
17
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.00457
AC:
1148
AN:
251250
Hom.:
7
AF XY:
0.00396
AC XY:
538
AN XY:
135868
show subpopulations
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 SAS exome
AF:
0.000849
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
show subpopulations
Gnomad4 AFR exome
AF:
0.0320
Gnomad4 AMR exome
AF:
0.00210
Gnomad4 ASJ exome
AF:
0.00207
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000858
Gnomad4 FIN exome
AF:
0.000318
Gnomad4 NFE exome
AF:
0.00377
Gnomad4 OTH exome
AF:
0.00518
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0112
AC:
1707
AN:
152264
Hom.:
18
Cov.:
32
AF XY:
0.0112
AC XY:
837
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.0321
Gnomad4 AMR
AF:
0.00503
Gnomad4 ASJ
AF:
0.00231
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.000471
Gnomad4 NFE
AF:
0.00354
Gnomad4 OTH
AF:
0.00427
Alfa
AF:
0.00668
Hom.:
8
Bravo
AF:
0.0128
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.00349
EpiControl
AF:
0.00415

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 31, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.38
Cadd
Benign
11
Dann
Benign
0.77
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs77633370; hg19: chr17-38510583; API