4-153466414-G-T

Variant names:

• chr4-153466414-G-T
• rs1269264340
• NM_001131007.2:c.17G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001131007.2(TMEM131L):​c.17G>T​(p.Arg6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000222 in 1,351,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: TMEM131L NM_001131007.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.486
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10059798).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001131007.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM131L	NM_001131007.2	MANE Select	c.17G>T	p.Arg6Leu	missense	Exon 1 of 35	NP_001124479.1	A2VDJ0-5
	TMEM131L	NM_015196.4		c.17G>T	p.Arg6Leu	missense	Exon 1 of 35	NP_056011.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM131L	ENST00000409959.8	TSL:5 MANE Select	c.17G>T	p.Arg6Leu	missense	Exon 1 of 35	ENSP00000386787.3	A2VDJ0-5
	TMEM131L	ENST00000409663.7	TSL:5	c.17G>T	p.Arg6Leu	missense	Exon 1 of 35	ENSP00000386574.3	A2VDJ0-1
	TMEM131L	ENST00000886543.1		c.17G>T	p.Arg6Leu	missense	Exon 1 of 35	ENSP00000556606.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151262 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.33e-7 AC: 1 AN: 1200328 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 586622

African (AFR) AF: 0.00 AC: 0 AN: 25036

American (AMR) AF: 0.00 AC: 0 AN: 19204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19226

East Asian (EAS) AF: 0.00 AC: 0 AN: 27378

South Asian (SAS) AF: 0.00 AC: 0 AN: 51890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3326

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 978544

Other (OTH) AF: 0.0000207 AC: 1 AN: 48272

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151262 Hom.: 0 Cov.: 32 AF XY: 0.0000271 AC XY: 2 AN XY: 73826

African (AFR) AF: 0.0000484 AC: 2 AN: 41360

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67522

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.49
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.019
Sift	Benign	0.35	T
Sift4G	Benign	0.27	T
Polyphen		0.14	B
Vest4		0.19
MutPred		0.35		Loss of glycosylation at P9 (P = 0.063)
MVP		0.043
MPC		0.19
ClinPred		0.20	T
GERP RS		0.36
PromoterAI		0.075	Neutral
Varity_R		0.14
gMVP		0.32
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs1269264340; hg19: chr4-154387566;