4-153558328-T-C

Variant names:

• chr4-153558328-T-C
• rs759428830
• NM_001131007.2:c.620T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001131007.2(TMEM131L):​c.620T>C​(p.Leu207Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,457,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TMEM131L NM_001131007.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.48

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4129863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM131L	NM_001131007.2	c.620T>C	p.Leu207Pro	missense_variant	Exon 7 of 35	ENST00000409959.8	NP_001124479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM131L	ENST00000409959.8	c.620T>C	p.Leu207Pro	missense_variant	Exon 7 of 35	5	NM_001131007.2	ENSP00000386787.3
TMEM131L	ENST00000240487.5	c.203T>C	p.Leu68Pro	missense_variant	Exon 3 of 29	1		ENSP00000240487.5
TMEM131L	ENST00000409663.7	c.620T>C	p.Leu207Pro	missense_variant	Exon 7 of 35	5		ENSP00000386574.3
TMEM131L	ENST00000462540.1	n.363T>C		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251392 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1457380 Hom.: 0 Cov.: 29 AF XY: 0.00000414 AC XY: 3 AN XY: 725010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.620T>C (p.L207P) alteration is located in exon 7 (coding exon 7) of the KIAA0922 gene. This alteration results from a T to C substitution at nucleotide position 620, causing the leucine (L) at amino acid position 207 to be replaced by a proline (P). 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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.015	T;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.70	N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.47
MutPred		0.54		Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);.;
MVP		0.093
MPC		0.32
ClinPred		0.89	D
GERP RS		6.0
Varity_R		0.28
gMVP		0.84

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: rs759428830; hg19: chr4-154479480;