4-153555894-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001131007.2(TMEM131L):c.416C>T(p.Pro139Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,551,154 control chromosomes in the GnomAD database, including 5 homozygotes. 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 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (5 hom.)
• Consequence: TMEM131L NM_001131007.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013923287).
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM131L	NM_001131007.2	c.416C>T	p.Pro139Leu	missense_variant	5/35	ENST00000409959.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM131L	ENST00000409959.8	c.416C>T	p.Pro139Leu	missense_variant	5/35	5	NM_001131007.2	A2

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 200 AN: 152006 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000945

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00223

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00134 AC: 210 AN: 156544 Hom.: 3 AF XY: 0.00131 AC XY: 109 AN XY: 82942

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.000488

Gnomad ASJ exome AF: 0.000588

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000395

Gnomad FIN exome AF: 0.000713

Gnomad NFE exome AF: 0.00272

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00220 AC: 3073 AN: 1399030 Hom.: 5 Cov.: 31 AF XY: 0.00203 AC XY: 1398 AN XY: 690048

Gnomad4 AFR exome AF: 0.000443

Gnomad4 AMR exome AF: 0.000729

Gnomad4 ASJ exome AF: 0.000397

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.00136

Gnomad4 NFE exome AF: 0.00263

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152124 Hom.: 0 Cov.: 31 AF XY: 0.00116 AC XY: 86 AN XY: 74366

Gnomad4 AFR AF: 0.000386

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.000945

Gnomad4 NFE AF: 0.00224

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00242 Hom.: 1

Bravo AF: 0.00137

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00314 AC: 10

ExAC AF: 0.00115 AC: 34

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Dec 08, 2023

The c.416C>T (p.P139L) alteration is located in exon 5 (coding exon 5) of the KIAA0922 gene. This alteration results from a C to T substitution at nucleotide position 416, causing the proline (P) at amino acid position 139 to be replaced by a leucine (L). 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	0.15
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	-0.038
Eigen_PC	Benign	-0.044
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.93	N;N
REVEL	Benign	0.18
Sift	Benign	0.048	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.97	D;D
Vest4		0.28
MVP		0.043
MPC		0.44
ClinPred		0.29	T
GERP RS		4.9
Varity_R		0.055
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs139597924; hg19: chr4-154477046; COSMIC: COSV99548520; COSMIC: COSV99548520;