4-153467211-C-T

Position:

• chr4-153467211-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.125C>T​(p.Ala42Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,551,634 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (13 hom.)
• Consequence: TMEM131L NM_001131007.2 missense, splice_region
• Scores: Splicing: ADA: 0.9797
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

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=0.005273938).
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM131L	NM_001131007.2	c.125C>T	p.Ala42Val	missense_variant, splice_region_variant	2/35	ENST00000409959.8	NP_001124479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM131L	ENST00000409959.8	c.125C>T	p.Ala42Val	missense_variant, splice_region_variant	2/35	5	NM_001131007.2	ENSP00000386787	A2
TMEM131L	ENST00000409663.7	c.125C>T	p.Ala42Val	missense_variant, splice_region_variant	2/35	5		ENSP00000386574	P4
TMEM131L	ENST00000445960.5	c.125C>T	p.Ala42Val	missense_variant, splice_region_variant, NMD_transcript_variant	2/5	4		ENSP00000413054

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 278 AN: 152170 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00146 AC: 225 AN: 154118 Hom.: 0 AF XY: 0.00149 AC XY: 122 AN XY: 81774

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.000942

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.000588

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00305 AC: 4274 AN: 1399346 Hom.: 13 Cov.: 31 AF XY: 0.00297 AC XY: 2052 AN XY: 690190

Gnomad4 AFR exome AF: 0.000633

Gnomad4 AMR exome AF: 0.000140

Gnomad4 ASJ exome AF: 0.000556

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00148

Gnomad4 NFE exome AF: 0.00373

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00183 AC: 278 AN: 152288 Hom.: 1 Cov.: 33 AF XY: 0.00165 AC XY: 123 AN XY: 74458

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00331

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00282 Hom.: 1

Bravo AF: 0.00165

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00471 AC: 15

ExAC AF: 0.00148 AC: 36

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

Feb 10, 2023

The c.125C>T (p.A42V) alteration is located in exon 2 (coding exon 2) of the KIAA0922 gene. This alteration results from a C to T substitution at nucleotide position 125, causing the alanine (A) at amino acid position 42 to be replaced by a valine (V). 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	0.14
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0043	T;.
Eigen	Benign	0.080
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	0.99	D;D;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.035
Sift	Benign	0.20	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.26	B;B
Vest4		0.17
MVP		0.043
MPC		0.12
ClinPred		0.80	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.72
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: rs78441178; hg19: chr4-154388363;