rs61741457

Variant names:

• chr8-133012033-C-T
• rs61741457
• NM_003235.5:c.6395C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-133012033-C-T
• chr8-133012033-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003235.5(TG):​c.6395C>T​(p.Ser2132Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 1,614,108 control chromosomes in the GnomAD database, including 2,617 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (177 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2440 hom.)
• Consequence: TG NM_003235.5 missense, splice_region
• Scores: Splicing: ADA: 0.0003433
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.291
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• thyroid dyshormonogenesis 3

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003029853).
• BP6: Variant 8-133012033-C-T is Benign according to our data. Variant chr8-133012033-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0595 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003235.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	NM_003235.5	MANE Select	c.6395C>T	p.Ser2132Leu	missense splice_region	Exon 36 of 48	NP_003226.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.6395C>T	p.Ser2132Leu	missense splice_region	Exon 36 of 48	ENSP00000220616.4	P01266-1
	TG	ENST00000523756.5	TSL:1	n.*2608C>T		splice_region non_coding_transcript_exon	Exon 23 of 35	ENSP00000428628.1	H0YB42
	TG	ENST00000523756.5	TSL:1	n.*2608C>T		3_prime_UTR	Exon 23 of 35	ENSP00000428628.1	H0YB42

Frequencies

GnomAD3 genomes AF: 0.0417 AC: 6339 AN: 152136 Hom.: 176 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0611

Gnomad OTH AF: 0.0473

GnomAD2 exomes AF: 0.0451 AC: 11336 AN: 251266 AF XY: 0.0475

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.0238

Gnomad ASJ exome AF: 0.0417

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0508

Gnomad NFE exome AF: 0.0611

Gnomad OTH exome AF: 0.0561

GnomAD4 exome AF: 0.0545 AC: 79741 AN: 1461854 Hom.: 2440 Cov.: 32 AF XY: 0.0550 AC XY: 40023 AN XY: 727238

African (AFR) AF: 0.0116 AC: 389 AN: 33480

American (AMR) AF: 0.0253 AC: 1131 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 1130 AN: 26134

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0517 AC: 4455 AN: 86244

European-Finnish (FIN) AF: 0.0507 AC: 2707 AN: 53412

Middle Eastern (MID) AF: 0.0829 AC: 478 AN: 5768

European-Non Finnish (NFE) AF: 0.0597 AC: 66348 AN: 1111996

Other (OTH) AF: 0.0511 AC: 3089 AN: 60396

GnomAD4 genome AF: 0.0417 AC: 6343 AN: 152254 Hom.: 177 Cov.: 32 AF XY: 0.0406 AC XY: 3025 AN XY: 74438

African (AFR) AF: 0.0136 AC: 567 AN: 41556

American (AMR) AF: 0.0365 AC: 558 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 129 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0516 AC: 249 AN: 4824

European-Finnish (FIN) AF: 0.0490 AC: 519 AN: 10594

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0611 AC: 4155 AN: 68006

Other (OTH) AF: 0.0468 AC: 99 AN: 2116

Alfa AF: 0.0505 Hom.: 528

Bravo AF: 0.0378

TwinsUK AF: 0.0628 AC: 233

ALSPAC AF: 0.0649 AC: 250

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.0609 AC: 524

ExAC AF: 0.0459 AC: 5577

Asia WGS AF: 0.0200 AC: 70 AN: 3478

EpiCase AF: 0.0622

EpiControl AF: 0.0614

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Iodotyrosyl coupling defect (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.74
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.5	N
PhyloP100		0.29
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.19
Sift	Benign	0.22	T
Sift4G	Benign	0.18	T
Polyphen		0.017	B
Vest4		0.15
MPC		0.062
ClinPred		0.0051	T
GERP RS		-7.2
Varity_R		0.10
gMVP		0.43
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61741457; hg19: chr8-134024278; COSMIC: COSV107274504;