4-153585514-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001131007.2(TMEM131L):c.1214C>G(p.Thr405Arg) 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: 32)
• Consequence: TMEM131L NM_001131007.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.279

Genes affected

TMEM131L (HGNC:29146): (transmembrane 131 like) Involved in negative regulation of canonical Wnt signaling pathway and negative regulation of immature T cell proliferation in thymus. Located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07128993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM131L	NM_001131007.2	c.1214C>G	p.Thr405Arg	missense_variant	13/35	ENST00000409959.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM131L	ENST00000409959.8	c.1214C>G	p.Thr405Arg	missense_variant	13/35	5	NM_001131007.2	A2
TMEM131L	ENST00000240487.5	c.797C>G	p.Thr266Arg	missense_variant	9/29	1
TMEM131L	ENST00000409663.7	c.1211C>G	p.Thr404Arg	missense_variant	13/35	5		P4
TMEM131L	ENST00000509565.1	n.289C>G		non_coding_transcript_exon_variant	3/4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 22, 2023

The c.1214C>G (p.T405R) alteration is located in exon 13 (coding exon 13) of the KIAA0922 gene. This alteration results from a C to G substitution at nucleotide position 1214, causing the threonine (T) at amino acid position 405 to be replaced by an arginine (R). 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	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	17
Dann	Benign	0.75
DEOGEN2	Benign	0.0035	T;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.071	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.59	P;P;.
Vest4		0.31
MutPred		0.25		Loss of glycosylation at S405 (P = 0.0213);.;.;
MVP		0.068
MPC		0.36
ClinPred		0.25	T
GERP RS		4.8
Varity_R		0.085
gMVP		0.57

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

Other links and lift over

dbSNP: rs1730642252; hg19: chr4-154506666;