dbSNP rs764976012: TAGLN3:p.Tyr103Cys (chr3-112000899-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001008272.2(TAGLN3):c.308A>G(p.Tyr103Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TAGLN3
NM_001008272.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.95

Publications

0 publications found

Variant links:

Genes affected

TAGLN3 (HGNC:29868): (transgelin 3) Predicted to be involved in central nervous system development. Predicted to act upstream of or within negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be active in cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

TAGLN3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAGLN3	NM_001008272.2 link	c.308A>G	p.Tyr103Cys	missense_variant	Exon 3 of 5	ENST00000478951.6	NP_001008273.1	Q9UI15
TAGLN3	NM_001008273.2 link	c.308A>G	p.Tyr103Cys	missense_variant	Exon 2 of 4		NP_001008274.1	Q9UI15
TAGLN3	NM_013259.3 link	c.308A>G	p.Tyr103Cys	missense_variant	Exon 3 of 5		NP_037391.2	Q9UI15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAGLN3	ENST00000478951.6 link	c.308A>G	p.Tyr103Cys	missense_variant	Exon 3 of 5	1	NM_001008272.2	ENSP00000419105.1		Q9UI15

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251480

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000479

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112002

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 17, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.308A>G (p.Y103C) alteration is located in exon 3 (coding exon 2) of the TAGLN3 gene. This alteration results from a A to G substitution at nucleotide position 308, causing the tyrosine (Y) at amino acid position 103 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

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;D;D;D;.;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

.;D;.;.;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H;H;H;.;.

PhyloP100

8.9

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-8.1

D;D;D;D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0040

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;.;.

Vest4

0.92

MutPred

0.76

Gain of glycosylation at T102 (P = 0.0435);Gain of glycosylation at T102 (P = 0.0435);Gain of glycosylation at T102 (P = 0.0435);Gain of glycosylation at T102 (P = 0.0435);.;.;

MVP

0.82

MPC

2.0

ClinPred

0.99

GERP RS

5.8

PromoterAI

-0.059

Neutral

(source)

Varity_R

0.68

gMVP

0.92

Mutation Taster

=30/70

disease causing

(source)

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

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rs764976012

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over