8-133050847-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001045556.3(SLA):c.130C>T(p.Arg44Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000298 in 1,612,784 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R44H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SLA NM_001045556.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4046842).
• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLA	NM_001045556.3	c.130C>T	p.Arg44Cys	missense_variant	4/9	ENST00000338087.10
TG	NM_003235.5	c.7239+20824G>A		intron_variant		ENST00000220616.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLA	ENST00000338087.10	c.130C>T	p.Arg44Cys	missense_variant	4/9	1	NM_001045556.3	P1
TG	ENST00000220616.9	c.7239+20824G>A		intron_variant		1	NM_003235.5	P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000288

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: 0.0000398 AC: 10 AN: 251420 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135880

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1460600 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 726728

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152184 Hom.: 1 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000288

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

Bravo AF: 0.000189

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2023

The c.250C>T (p.R84C) alteration is located in exon 2 (coding exon 2) of the SLA gene. This alteration results from a C to T substitution at nucleotide position 250, causing the arginine (R) at amino acid position 84 to be replaced by a cysteine (C). 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	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;.;.;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-4.4	D;D;D;D;D;D;D
REVEL	Benign	0.23
Sift	Benign	0.085	T;T;T;T;T;D;D
Sift4G	Uncertain	0.043	D;D;D;T;.;.;.
Polyphen		1.0	D;.;.;.;D;D;.
Vest4		0.56
MutPred		0.38		Loss of disorder (P = 0.0274);.;.;.;Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);
MVP		0.51
MPC		0.86
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.16
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772751614; hg19: chr8-134063092; COSMIC: COSV55099555; COSMIC: COSV55099555;