8-133038655-C-T

Variant names:

• chr8-133038655-C-T
• NM_001045556.3:c.700G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001045556.3(SLA):​c.700G>A​(p.Ala234Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLA NM_001045556.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27327853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLA	NM_001045556.3	c.700G>A	p.Ala234Thr	missense_variant	Exon 9 of 9	ENST00000338087.10	NP_001039021.1
TG	NM_003235.5	c.7239+8632C>T		intron_variant	Intron 41 of 47	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLA	ENST00000338087.10	c.700G>A	p.Ala234Thr	missense_variant	Exon 9 of 9	1	NM_001045556.3	ENSP00000337548.5
TG	ENST00000220616.9	c.7239+8632C>T		intron_variant	Intron 41 of 47	1	NM_003235.5	ENSP00000220616.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.820G>A (p.A274T) alteration is located in exon 7 (coding exon 7) of the SLA gene. This alteration results from a G to A substitution at nucleotide position 820, causing the alanine (A) at amino acid position 274 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;.;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D;D;D;D;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.2	M;.;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.10	T;T;T;T;T
Sift4G	Uncertain	0.027	D;D;D;D;D
Polyphen		0.99	D;.;.;.;.
Vest4		0.26
MutPred		0.19		Gain of disorder (P = 0.0621);.;.;.;.;
MVP		0.51
MPC		0.79
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.21
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-134050900;