rs767704779

Variant names:

• chr8-133047916-A-C
• rs767704779
• NM_001045556.3:c.266T>G

Your query was ambiguous. Multiple possible variants found:

• chr8-133047916-A-C
• chr8-133047916-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001045556.3(SLA):​c.266T>G​(p.Leu89Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L89P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLA NM_001045556.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.87
• Publications: 0 publications found

Genes affected

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]

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: 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001045556.3. 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
	SLA	NM_001045556.3	MANE Select	c.266T>G	p.Leu89Arg	missense	Exon 6 of 9	NP_001039021.1	Q13239-1
	TG	NM_003235.5	MANE Select	c.7239+17893A>C		intron	N/A	NP_003226.4
	SLA	NM_006748.4		c.386T>G	p.Leu129Arg	missense	Exon 4 of 7	NP_006739.2	Q13239-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLA	ENST00000338087.10	TSL:1 MANE Select	c.266T>G	p.Leu89Arg	missense	Exon 6 of 9	ENSP00000337548.5	Q13239-1
	SLA	ENST00000427060.6	TSL:1	c.386T>G	p.Leu129Arg	missense	Exon 4 of 7	ENSP00000394049.2	Q13239-5
	SLA	ENST00000395352.7	TSL:1	c.317T>G	p.Leu106Arg	missense	Exon 5 of 8	ENSP00000378759.3	Q13239-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		8.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.88		Gain of disorder (P = 0.0292)
MVP		0.89
MPC		1.0
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.83
gMVP		0.83
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs767704779; hg19: chr8-134060161;