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GeneBe

17-40083963-C-T

Variant summary

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

The NM_199334.5(THRA):c.351C>T(p.Ala117=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0447 in 1,613,222 control chromosomes in the GnomAD database, including 1,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.040 ( 151 hom., cov: 32)
Exomes 𝑓: 0.045 ( 1718 hom. )

Consequence

THRA
NM_199334.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -5.76
Variant links:
Genes affected
THRA (HGNC:11796): (thyroid hormone receptor alpha) The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

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=-0.31).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-40083963-C-T is Benign according to our data. Variant chr17-40083963-C-T is described in ClinVar as [Benign]. Clinvar id is 259020.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-40083963-C-T is described in Lovd as [Benign].
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=-5.76 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0395 (6022/152266) while in subpopulation NFE AF= 0.0482 (3280/68004). AF 95% confidence interval is 0.0469. There are 151 homozygotes in gnomad4. There are 2796 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 6002 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
THRANM_199334.5 linkuse as main transcriptc.351C>T p.Ala117= synonymous_variant 5/9 ENST00000450525.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
THRAENST00000450525.7 linkuse as main transcriptc.351C>T p.Ala117= synonymous_variant 5/91 NM_199334.5 P1P10827-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0394
AC:
6002
AN:
152148
Hom.:
147
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0381
Gnomad AMI
AF:
0.0318
Gnomad AMR
AF:
0.0240
Gnomad ASJ
AF:
0.0144
Gnomad EAS
AF:
0.00539
Gnomad SAS
AF:
0.0254
Gnomad FIN
AF:
0.0439
Gnomad MID
AF:
0.0190
Gnomad NFE
AF:
0.0482
Gnomad OTH
AF:
0.0363
GnomAD3 exomes
AF:
0.0365
AC:
9131
AN:
250440
Hom.:
193
AF XY:
0.0361
AC XY:
4882
AN XY:
135380
show subpopulations
Gnomad AFR exome
AF:
0.0396
Gnomad AMR exome
AF:
0.0182
Gnomad ASJ exome
AF:
0.0181
Gnomad EAS exome
AF:
0.00802
Gnomad SAS exome
AF:
0.0350
Gnomad FIN exome
AF:
0.0435
Gnomad NFE exome
AF:
0.0468
Gnomad OTH exome
AF:
0.0371
GnomAD4 exome
AF:
0.0452
AC:
66057
AN:
1460956
Hom.:
1718
Cov.:
30
AF XY:
0.0443
AC XY:
32173
AN XY:
726788
show subpopulations
Gnomad4 AFR exome
AF:
0.0411
Gnomad4 AMR exome
AF:
0.0194
Gnomad4 ASJ exome
AF:
0.0177
Gnomad4 EAS exome
AF:
0.00358
Gnomad4 SAS exome
AF:
0.0324
Gnomad4 FIN exome
AF:
0.0463
Gnomad4 NFE exome
AF:
0.0498
Gnomad4 OTH exome
AF:
0.0416
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0395
AC:
6022
AN:
152266
Hom.:
151
Cov.:
32
AF XY:
0.0376
AC XY:
2796
AN XY:
74424
show subpopulations
Gnomad4 AFR
AF:
0.0385
Gnomad4 AMR
AF:
0.0240
Gnomad4 ASJ
AF:
0.0144
Gnomad4 EAS
AF:
0.00541
Gnomad4 SAS
AF:
0.0255
Gnomad4 FIN
AF:
0.0439
Gnomad4 NFE
AF:
0.0482
Gnomad4 OTH
AF:
0.0360
Alfa
AF:
0.0447
Hom.:
113
Bravo
AF:
0.0383
Asia WGS
AF:
0.0420
AC:
145
AN:
3478
EpiCase
AF:
0.0415
EpiControl
AF:
0.0412

ClinVar

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

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 18, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.31
Cadd
Benign
10
Dann
Benign
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs2230701; hg19: chr17-38240216; COSMIC: COSV52843038; COSMIC: COSV52843038; API