Genetic Variant NM_003235.5:c.7240-152T>G (chr8-133094892-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003235.5(TG):c.7240-152T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 989,948 control chromosomes in the GnomAD database, including 256,414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 41545 hom., cov: 32)

Exomes 𝑓: 0.71 ( 214869 hom. )

Consequence

TG
NM_003235.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.75

Variant links:

Genes affected

TG (HGNC:11764): (thyroglobulin) Thyroglobulin (Tg) is a glycoprotein homodimer produced predominantly by the thryroid gland. It acts as a substrate for the synthesis of thyroxine and triiodothyronine as well as the storage of the inactive forms of thyroid hormone and iodine. Thyroglobulin is secreted from the endoplasmic reticulum to its site of iodination, and subsequent thyroxine biosynthesis, in the follicular lumen. Mutations in this gene cause thyroid dyshormonogenesis, manifested as goiter, and are associated with moderate to severe congenital hypothyroidism. Polymorphisms in this gene are associated with susceptibility to autoimmune thyroid diseases (AITD) such as Graves disease and Hashimoto thryoiditis. [provided by RefSeq, Nov 2009]

TG links:

SLA (HGNC:10902): (Src like adaptor) Predicted to enable signaling receptor binding activity. Predicted to be involved in cell differentiation; innate immune response; and transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to be located in cytosol. Predicted to be active in dendritic spine and focal adhesion. Predicted to be extrinsic component of cytoplasmic side of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 8-133094892-T-G is Benign according to our data. Variant chr8-133094892-T-G is described in ClinVar as [Benign]. Clinvar id is 1248250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5 link	c.7240-152T>G		intron_variant	Intron 41 of 47	ENST00000220616.9	NP_003226.4	P01266-1
SLA	NM_001045556.3 link	c.-319+7661A>C		intron_variant	Intron 1 of 8	ENST00000338087.10	NP_001039021.1	Q13239-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9 link	c.7240-152T>G		intron_variant	Intron 41 of 47	1	NM_003235.5	ENSP00000220616.4		P01266-1
SLA	ENST00000338087.10 link	c.-319+7661A>C		intron_variant	Intron 1 of 8	1	NM_001045556.3	ENSP00000337548.5		Q13239-1

Frequencies

GnomAD3 genomes

AF:

0.734

AC:

111610

AN:

151976

Hom.:

41503

Cov.:

show subpopulations

Gnomad AFR

AF:

0.810

Gnomad AMI

AF:

0.697

Gnomad AMR

AF:

0.648

Gnomad ASJ

AF:

0.793

Gnomad EAS

AF:

0.426

Gnomad SAS

AF:

0.600

Gnomad FIN

AF:

0.703

Gnomad MID

AF:

0.756

Gnomad NFE

AF:

0.743

Gnomad OTH

AF:

0.738

GnomAD4 exome

AF:

0.710

AC:

595053

AN:

837854

Hom.:

214869

Cov.:

AF XY:

0.708

AC XY:

310586

AN XY:

438934

show subpopulations

Gnomad4 AFR exome

AF:

0.816

Gnomad4 AMR exome

AF:

0.581

Gnomad4 ASJ exome

AF:

0.796

Gnomad4 EAS exome

AF:

0.383

Gnomad4 SAS exome

AF:

0.612

Gnomad4 FIN exome

AF:

0.703

Gnomad4 NFE exome

AF:

0.745

Gnomad4 OTH exome

AF:

0.724

GnomAD4 genome

AF:

0.734

AC:

111698

AN:

152094

Hom.:

41545

Cov.:

AF XY:

0.727

AC XY:

54034

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.810

Gnomad4 AMR

AF:

0.648

Gnomad4 ASJ

AF:

0.793

Gnomad4 EAS

AF:

0.426

Gnomad4 SAS

AF:

0.602

Gnomad4 FIN

AF:

0.703

Gnomad4 NFE

AF:

0.743

Gnomad4 OTH

AF:

0.732

Alfa

AF:

0.709

Hom.:

5137

Bravo

AF:

0.730

Asia WGS

AF:

0.516

AC:

1799

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

8.8

DANN

Benign

0.43

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over