chr4-153467211-C-T

Variant names:

• chr4-153467211-C-T
• rs78441178
• NM_001131007.2:c.125C>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.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. 15/24 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
• Publications: 4 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=0.005273938).
• BS2: High Homozygotes in GnomAdExome4 at 13 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.125C>T	p.Ala42Val	missense splice_region	Exon 2 of 35	NP_001124479.1	A2VDJ0-5
	TMEM131L	NM_015196.4		c.125C>T	p.Ala42Val	missense splice_region	Exon 2 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.125C>T	p.Ala42Val	missense splice_region	Exon 2 of 35	ENSP00000386787.3	A2VDJ0-5
	TMEM131L	ENST00000409663.7	TSL:5	c.125C>T	p.Ala42Val	missense splice_region	Exon 2 of 35	ENSP00000386574.3	A2VDJ0-1
	TMEM131L	ENST00000886543.1		c.125C>T	p.Ala42Val	missense splice_region	Exon 2 of 35	ENSP00000556606.1

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

GnomAD2 exomes AF: 0.00146 AC: 225 AN: 154118 AF XY: 0.00149

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 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

African (AFR) AF: 0.000633 AC: 20 AN: 31588

American (AMR) AF: 0.000140 AC: 5 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.000556 AC: 14 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79234

European-Finnish (FIN) AF: 0.00148 AC: 73 AN: 49298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00373 AC: 4019 AN: 1078900

Other (OTH) AF: 0.00243 AC: 141 AN: 58012

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

African (AFR) AF: 0.000602 AC: 25 AN: 41548

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00331 AC: 225 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00264 Hom.: 2

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

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	-0.59	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
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.035
Sift	Benign	0.20	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.26	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
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs78441178; hg19: chr4-154388363;