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GeneBe

8-109087635-A-G

Variant summary

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

The NM_003301.7(TRHR):c.123A>G(p.Val41=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,614,168 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0037 ( 9 hom. )

Consequence

TRHR
NM_003301.7 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.459
Variant links:
Genes affected
TRHR (HGNC:12299): (thyrotropin releasing hormone receptor) This gene encodes a G protein-coupled receptor for thyrotropin-releasing hormone (TRH). Upon binding to TRH, this receptor activates the inositol phospholipid-calcium-protein kinase C transduction pathway. Mutations in this gene have been associated with generalized thyrotropin-releasing hormone resistance. [provided by RefSeq, Sep 2011]

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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=-0.56).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 8-109087635-A-G is Benign according to our data. Variant chr8-109087635-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 715012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-109087635-A-G 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=0.459 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 Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TRHRNM_003301.7 linkuse as main transcriptc.123A>G p.Val41= synonymous_variant 2/3 ENST00000518632.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TRHRENST00000518632.2 linkuse as main transcriptc.123A>G p.Val41= synonymous_variant 2/35 NM_003301.7 P1
TRHRENST00000311762.2 linkuse as main transcriptc.123A>G p.Val41= synonymous_variant 1/21 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00217
AC:
330
AN:
152164
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000507
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.00424
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00378
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00209
AC:
526
AN:
251386
Hom.:
2
AF XY:
0.00216
AC XY:
294
AN XY:
135868
show subpopulations
Gnomad AFR exome
AF:
0.000369
Gnomad AMR exome
AF:
0.000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000621
Gnomad FIN exome
AF:
0.00319
Gnomad NFE exome
AF:
0.00357
Gnomad OTH exome
AF:
0.00261
GnomAD4 exome
AF:
0.00366
AC:
5352
AN:
1461886
Hom.:
9
Cov.:
31
AF XY:
0.00352
AC XY:
2562
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.000329
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000661
Gnomad4 FIN exome
AF:
0.00324
Gnomad4 NFE exome
AF:
0.00447
Gnomad4 OTH exome
AF:
0.00205
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00217
AC:
330
AN:
152282
Hom.:
2
Cov.:
32
AF XY:
0.00212
AC XY:
158
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.000505
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000622
Gnomad4 FIN
AF:
0.00424
Gnomad4 NFE
AF:
0.00378
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00286
Hom.:
0
Bravo
AF:
0.00177
EpiCase
AF:
0.00316
EpiControl
AF:
0.00302

ClinVar

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

Submissions by phenotype

TRHR-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 22, 2024This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
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
-0.56
Cadd
Benign
7.2
Dann
Benign
0.65

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: rs5775; hg19: chr8-110099864; COSMIC: COSV61236283; API