4-153583670-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001131007.2(TMEM131L):c.1058A>G(p.Lys353Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000553 in 1,537,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: TMEM131L NM_001131007.2 missense, splice_region
• Scores: Splicing: ADA: 0.0004459
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.01

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.065641314).
• BP6: Variant 4-153583670-A-G is Benign according to our data. Variant chr4-153583670-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3178589.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM131L	NM_001131007.2	c.1058A>G	p.Lys353Arg	missense_variant, splice_region_variant	11/35	ENST00000409959.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM131L	ENST00000409959.8	c.1058A>G	p.Lys353Arg	missense_variant, splice_region_variant	11/35	5	NM_001131007.2	A2
TMEM131L	ENST00000240487.5	c.641A>G	p.Lys214Arg	missense_variant, splice_region_variant	7/29	1
TMEM131L	ENST00000409663.7	c.1058A>G	p.Lys353Arg	missense_variant, splice_region_variant	11/35	5		P4
TMEM131L	ENST00000509565.1	n.133A>G		splice_region_variant, non_coding_transcript_exon_variant	1/4	4

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000125 AC: 3 AN: 240584 Hom.: 0 AF XY: 0.0000230 AC XY: 3 AN XY: 130200

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: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000577 AC: 80 AN: 1385632 Hom.: 0 Cov.: 23 AF XY: 0.0000635 AC XY: 44 AN XY: 692972

Gnomad4 AFR exome AF: 0.0000318

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: 0.0000753

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74350

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000761 Hom.: 0

Bravo AF: 0.0000567

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	8.0
Dann	Benign	0.85
DEOGEN2	Benign	0.0032	T;.;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.82
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.066	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	0.51	D;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.77	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.65	T;T;T
Polyphen		0.0080	B;B;.
Vest4		0.13
MVP		0.068
MPC		0.093
ClinPred		0.036	T
GERP RS		-1.2
Varity_R		0.030
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00045
dbscSNV1_RF	Benign	0.048
SpliceAI score (max)		0.010		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: rs891288554; hg19: chr4-154504822;