chr8-133060136-G-T

Position:

chr8-133060136-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001045556.3(SLA):c.25C>A(p.Pro9Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000645 in 1,611,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

SLA
NM_001045556.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.06

Variant links:

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]

SLA links:

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 links:

SLA (HGNC:):

SLA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04612276).

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLA	NM_001045556.3 linkuse as main transcript	c.25C>A	p.Pro9Thr	missense_variant	3/9	ENST00000338087.10	NP_001039021.1	Q13239-1
TG	NM_003235.5 linkuse as main transcript	c.7239+30113G>T		intron_variant		ENST00000220616.9	NP_003226.4	P01266-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLA	ENST00000338087.10 linkuse as main transcript	c.25C>A	p.Pro9Thr	missense_variant	3/9	1	NM_001045556.3	ENSP00000337548.5		Q13239-1
TG	ENST00000220616.9 linkuse as main transcript	c.7239+30113G>T		intron_variant		1	NM_003235.5	ENSP00000220616.4		P01266-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

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:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000804

AC:

AN:

248630

Hom.:

AF XY:

0.0000744

AC XY:

AN XY:

134476

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000416

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:

0.0000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000569

AC:

AN:

1459362

Hom.:

Cov.:

AF XY:

0.0000496

AC XY:

AN XY:

726030

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000365

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.000138

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000965

Hom.:

Bravo

AF:

0.000219

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2024

The c.145C>A (p.P49T) alteration is located in exon 1 (coding exon 1) of the SLA gene. This alteration results from a C to A substitution at nucleotide position 145, causing the proline (P) at amino acid position 49 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

0.058

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.32

CADD

Benign

7.2

DANN

Benign

0.80

DEOGEN2

Benign

0.26

T;.;.;.;.;.;.;.;.;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.74

T;T;T;T;T;T;T;T;T;.

M_CAP

Benign

0.016

MetaRNN

Benign

0.046

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.41

N;.;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.3

N;N;N;N;N;N;N;D;D;D

REVEL

Benign

0.076

Sift

Benign

0.20

T;T;T;T;T;T;T;T;D;.

Sift4G

Benign

0.54

T;T;T;T;.;.;.;.;.;.

Polyphen

0.0

B;.;.;.;B;B;.;.;.;.

Vest4

0.13

MutPred

0.14

Gain of phosphorylation at P9 (P = 0.0283);.;.;.;Gain of phosphorylation at P9 (P = 0.0283);Gain of phosphorylation at P9 (P = 0.0283);Gain of phosphorylation at P9 (P = 0.0283);Gain of phosphorylation at P9 (P = 0.0283);Gain of phosphorylation at P9 (P = 0.0283);Gain of phosphorylation at P9 (P = 0.0283);

MVP

0.25

MPC

0.25

ClinPred

0.021

GERP RS

1.4

Varity_R

0.034

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over