chr8-133050904-C-T

Position:

• chr8-133050904-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001045556.3(SLA):​c.73G>A​(p.Asp25Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000633 in 1,611,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: SLA NM_001045556.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.01

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16827947).
• BS2: High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLA	NM_001045556.3	c.73G>A	p.Asp25Asn	missense_variant	4/9	ENST00000338087.10
TG	NM_003235.5	c.7239+20881C>T		intron_variant		ENST00000220616.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLA	ENST00000338087.10	c.73G>A	p.Asp25Asn	missense_variant	4/9	1	NM_001045556.3	P1
TG	ENST00000220616.9	c.7239+20881C>T		intron_variant		1	NM_003235.5	P1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000957

GnomAD3 exomes AF: 0.0000796 AC: 20 AN: 251240 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135800

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000432 AC: 63 AN: 1459666 Hom.: 0 Cov.: 29 AF XY: 0.0000413 AC XY: 30 AN XY: 726344

Gnomad4 AFR exome AF: 0.000688

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74422

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.000131

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: 0.000947

Alfa AF: 0.0000461 Hom.: 0

Bravo AF: 0.000317

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Feb 03, 2022

The c.193G>A (p.D65N) alteration is located in exon 2 (coding exon 2) of the SLA gene. This alteration results from a G to A substitution at nucleotide position 193, causing the aspartic acid (D) at amino acid position 65 to be replaced by an asparagine (N). 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	0.28
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.3	L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.72	N;N;N;N;N;N;D;D;D
REVEL	Benign	0.17
Sift	Benign	0.17	T;T;T;D;T;T;D;D;D
Sift4G	Benign	0.21	T;T;T;T;.;.;.;.;.
Polyphen		1.0	D;.;.;.;D;D;.;.;.
Vest4		0.59
MVP		0.81
MPC		0.81
ClinPred		0.13	T
GERP RS		5.4
Varity_R		0.10
gMVP		0.52

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: rs148579032; hg19: chr8-134063149;