chr9-35698343-C-G

Variant names:

• chr9-35698343-C-G
• NM_006289.4:c.7351G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006289.4(TLN1):​c.7351G>C​(p.Glu2451Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLN1 NM_006289.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85
• Publications: 0 publications found

Genes affected

TLN1 (HGNC:11845): (talin 1) This gene encodes a cytoskeletal protein that is concentrated in areas of cell-substratum and cell-cell contacts. The encoded protein plays a significant role in the assembly of actin filaments and in spreading and migration of various cell types, including fibroblasts and osteoclasts. It codistributes with integrins in the cell surface membrane in order to assist in the attachment of adherent cells to extracellular matrices and of lymphocytes to other cells. The N-terminus of this protein contains elements for localization to cell-extracellular matrix junctions. The C-terminus contains binding sites for proteins such as beta-1-integrin, actin, and vinculin. [provided by RefSeq, Feb 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18366218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLN1	NM_006289.4	c.7351G>C	p.Glu2451Gln	missense_variant	Exon 55 of 57	ENST00000314888.10	NP_006280.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLN1	ENST00000314888.10	c.7351G>C	p.Glu2451Gln	missense_variant	Exon 55 of 57	1	NM_006289.4	ENSP00000316029.9
TLN1	ENST00000706939.1	c.7402G>C	p.Glu2468Gln	missense_variant	Exon 56 of 58			ENSP00000516659.1
TLN1	ENST00000489255.2	n.649G>C		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7351G>C (p.E2451Q) alteration is located in exon 55 (coding exon 54) of the TLN1 gene. This alteration results from a G to C substitution at nucleotide position 7351, causing the glutamic acid (E) at amino acid position 2451 to be replaced by a glutamine (Q). 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	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.40	N
PhyloP100		4.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.049
Sift	Benign	0.19	T
Sift4G	Benign	0.27	T
Polyphen		0.0050	B
Vest4		0.12
MutPred		0.36		Gain of MoRF binding (P = 0.0241);
MVP		0.36
MPC		0.51
ClinPred		0.47	T
GERP RS		4.9
Varity_R		0.16
gMVP		0.39
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

hg19: chr9-35698340;