8-133050908-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001045556.3(SLA):c.69T>G(p.Asp23Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,611,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SLA NM_001045556.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.189

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04638955).
• BP6: Variant 8-133050908-A-C is Benign according to our data. Variant chr8-133050908-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3162692.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLA	NM_001045556.3	c.69T>G	p.Asp23Glu	missense_variant	4/9	ENST00000338087.10
TG	NM_003235.5	c.7239+20885A>C		intron_variant		ENST00000220616.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLA	ENST00000338087.10	c.69T>G	p.Asp23Glu	missense_variant	4/9	1	NM_001045556.3	P1
TG	ENST00000220616.9	c.7239+20885A>C		intron_variant		1	NM_003235.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251268 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135796

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1458888 Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9 AN XY: 725992

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74488

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000166

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.049
Dann	Benign	0.48
DEOGEN2	Benign	0.14	T;.;.;.;.;.;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.58	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.046	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.59	N;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.33	N;N;N;N;N;N;N;N;D
REVEL	Benign	0.18
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.64	T;T;T;T;.;.;.;.;.
Polyphen		0.0	B;.;.;.;B;B;.;.;.
Vest4		0.11
MutPred		0.16		Loss of glycosylation at S24 (P = 0.096);.;.;.;Loss of glycosylation at S24 (P = 0.096);Loss of glycosylation at S24 (P = 0.096);Loss of glycosylation at S24 (P = 0.096);Loss of glycosylation at S24 (P = 0.096);Loss of glycosylation at S24 (P = 0.096);
MVP		0.47
MPC		0.21
ClinPred		0.047	T
GERP RS		-0.48
Varity_R		0.029
gMVP		0.14

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

Other links and lift over

dbSNP: rs756605930; hg19: chr8-134063153;