10-25023857-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024838.5(THNSL1):c.634G>A(p.Val212Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: THNSL1 NM_024838.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53

Genes affected

THNSL1 (HGNC:26160): (threonine synthase like 1)

ENKUR (HGNC:28388): (enkurin, TRPC channel interacting protein) This gene encodes a protein that interacts with calmodulin and several transient receptor potential canonical cation channel proteins. The encoded protein may function as an adaptor to localize signal transduction machinery to calcium channels. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066351354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THNSL1	NM_024838.5	c.634G>A	p.Val212Ile	missense_variant	3/3	ENST00000376356.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THNSL1	ENST00000376356.5	c.634G>A	p.Val212Ile	missense_variant	3/3	1	NM_024838.5	P1
ENKUR	ENST00000615958.4	c.38-27988C>T		intron_variant		1
THNSL1	ENST00000524413.5	c.634G>A	p.Val212Ile	missense_variant	3/3	3		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

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

Mar 01, 2023

The c.634G>A (p.V212I) alteration is located in exon 3 (coding exon 1) of the THNSL1 gene. This alteration results from a G to A substitution at nucleotide position 634, causing the valine (V) at amino acid position 212 to be replaced by an isoleucine (I). 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	0.082
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	13
Dann	Benign	0.89
DEOGEN2	Benign	0.00075	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.93	L;L
MutationTaster	Benign	0.69	D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.15	N;N
REVEL	Benign	0.068
Sift	Benign	0.33	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.0040	B;B
Vest4		0.12
MutPred		0.55		Loss of ubiquitination at K215 (P = 0.1322);Loss of ubiquitination at K215 (P = 0.1322);
MVP		0.095
MPC		0.025
ClinPred		0.33	T
GERP RS		-0.86
Varity_R		0.053
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-25312786;