4-153555894-C-T

Variant names:

• chr4-153555894-C-T
• rs139597924
• NM_001131007.2:c.416C>T

Variant summary

Our verdict is Benign. The variant received -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. 15/22 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
• Publications: 3 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013923287).
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.416C>T	p.Pro139Leu	missense	Exon 5 of 35	NP_001124479.1	A2VDJ0-5
	TMEM131L	NM_015196.4		c.416C>T	p.Pro139Leu	missense	Exon 5 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.416C>T	p.Pro139Leu	missense	Exon 5 of 35	ENSP00000386787.3	A2VDJ0-5
	TMEM131L	ENST00000409663.7	TSL:5	c.416C>T	p.Pro139Leu	missense	Exon 5 of 35	ENSP00000386574.3	A2VDJ0-1
	TMEM131L	ENST00000886543.1		c.416C>T	p.Pro139Leu	missense	Exon 5 of 35	ENSP00000556606.1

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

GnomAD2 exomes AF: 0.00134 AC: 210 AN: 156544 AF XY: 0.00131

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 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

African (AFR) AF: 0.000443 AC: 14 AN: 31590

American (AMR) AF: 0.000729 AC: 26 AN: 35674

Ashkenazi Jewish (ASJ) AF: 0.000397 AC: 10 AN: 25170

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35716

South Asian (SAS) AF: 0.000202 AC: 16 AN: 79204

European-Finnish (FIN) AF: 0.00136 AC: 67 AN: 49276

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5692

European-Non Finnish (NFE) AF: 0.00263 AC: 2841 AN: 1078728

Other (OTH) AF: 0.00167 AC: 97 AN: 57980

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

African (AFR) AF: 0.000386 AC: 16 AN: 41478

American (AMR) AF: 0.000851 AC: 13 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4812

European-Finnish (FIN) AF: 0.000945 AC: 10 AN: 10582

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00224 AC: 152 AN: 68008

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00228 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

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	0.15
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
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.8
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.18
Sift	Benign	0.048	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.97	D
Vest4		0.28
MVP		0.043
MPC		0.44
ClinPred		0.29	T
GERP RS		4.9
PromoterAI		0.033	Neutral
Varity_R		0.055
gMVP		0.42
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs139597924; hg19: chr4-154477046; COSMIC: COSV99548520; COSMIC: COSV99548520;