3-24146858-A-G

Variant names:

• chr3-24146858-A-G
• rs79187081
• NM_001354712.2:c.385-36T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001354712.2(THRB):​c.385-36T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,604,550 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0083 (9 hom., cov: 32)
  • Exomes 𝑓: 0.010 (99 hom.)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.16

Genes affected

THRB (HGNC:11799): (thyroid hormone receptor beta) 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. Mutations in this gene are known to be a cause of generalized thyroid hormone resistance (GTHR), a syndrome characterized by goiter and high levels of circulating thyroid hormone (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH). Several alternatively spliced transcript variants encoding the same protein have been observed for this gene. [provided by RefSeq, Jul 2008]

ENSG00000289130 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-24146858-A-G is Benign according to our data. Variant chr3-24146858-A-G is described in ClinVar as [Benign]. Clinvar id is 993242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00829 (1263/152320) while in subpopulation NFE AF= 0.0118 (801/68022). AF 95% confidence interval is 0.0111. There are 9 homozygotes in gnomad4. There are 634 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRB	NM_001354712.2	c.385-36T>C		intron_variant	Intron 6 of 10	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.385-36T>C		intron_variant	Intron 6 of 10		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes AF: 0.00830 AC: 1263 AN: 152202 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00941 AC: 2347 AN: 249402 Hom.: 15 AF XY: 0.0101 AC XY: 1361 AN XY: 135164

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.00798

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.00721

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0102 AC: 14853 AN: 1452230 Hom.: 99 Cov.: 27 AF XY: 0.0103 AC XY: 7417 AN XY: 723146

Gnomad4 AFR exome AF: 0.00156

Gnomad4 AMR exome AF: 0.00847

Gnomad4 ASJ exome AF: 0.0180

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00776

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.00829 AC: 1263 AN: 152320 Hom.: 9 Cov.: 32 AF XY: 0.00851 AC XY: 634 AN XY: 74486

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.0132

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00643

Gnomad4 FIN AF: 0.0137

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0116 Hom.: 1

Bravo AF: 0.00732

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Apr 13, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.82
BranchPoint Hunter		3.0

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

Other links and lift over

dbSNP: rs79187081; hg19: chr3-24188349;