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rs41283431

chr17-40088256-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_199334.5(THRA):c.738C>T(p.Asp246=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,593,706 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 1 hom., cov: 31)
Exomes 𝑓: 0.0043 ( 16 hom. )

Consequence

THRA
NM_199334.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.13
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 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=-0.48).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-40088256-C-T is Benign according to our data. Variant chr17-40088256-C-T is described in ClinVar as [Benign]. Clinvar id is 259021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-40088256-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=2.13 with no splicing effect.
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 487 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
THRANM_199334.5 linkuse as main transcriptc.738C>T p.Asp246= synonymous_variant 8/9 ENST00000450525.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
THRAENST00000450525.7 linkuse as main transcriptc.738C>T p.Asp246= synonymous_variant 8/91 NM_199334.5 P1P10827-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00320
AC:
487
AN:
152220
Hom.:
1
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00386
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00753
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.00451
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00351
AC:
832
AN:
236908
Hom.:
1
AF XY:
0.00352
AC XY:
448
AN XY:
127314
show subpopulations
Gnomad AFR exome
AF:
0.000371
Gnomad AMR exome
AF:
0.00191
Gnomad ASJ exome
AF:
0.00143
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000402
Gnomad FIN exome
AF:
0.00750
Gnomad NFE exome
AF:
0.00523
Gnomad OTH exome
AF:
0.00452
GnomAD4 exome
AF:
0.00430
AC:
6203
AN:
1441368
Hom.:
16
Cov.:
32
AF XY:
0.00423
AC XY:
3025
AN XY:
714408
show subpopulations
Gnomad4 AFR exome
AF:
0.000572
Gnomad4 AMR exome
AF:
0.00232
Gnomad4 ASJ exome
AF:
0.00110
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.000337
Gnomad4 FIN exome
AF:
0.00711
Gnomad4 NFE exome
AF:
0.00485
Gnomad4 OTH exome
AF:
0.00410
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00319
AC:
486
AN:
152338
Hom.:
1
Cov.:
31
AF XY:
0.00293
AC XY:
218
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.000577
Gnomad4 AMR
AF:
0.00385
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00753
Gnomad4 NFE
AF:
0.00451
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00318
Hom.:
0
Bravo
AF:
0.00284
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
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
-0.48
Cadd
Benign
13
Dann
Benign
0.89
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs41283431; hg19: chr17-38244509; API