19-18616019-C-A

Position:

• chr19-18616019-C-A

Variant summary

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

The NM_012109.3(TMEM59L):​c.453C>A​(p.Asp151Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM59L NM_012109.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.178

Genes affected

TMEM59L (HGNC:13237): (transmembrane protein 59 like) This gene encodes a predicted type-I membrane glycoprotein. The encoded protein may play a role in functioning of the central nervous system. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026621759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM59L	NM_012109.3	c.453C>A	p.Asp151Glu	missense_variant	4/8	ENST00000262817.8	NP_036241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM59L	ENST00000262817.8	c.453C>A	p.Asp151Glu	missense_variant	4/8	1	NM_012109.3	ENSP00000262817	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2023

The c.453C>A (p.D151E) alteration is located in exon 4 (coding exon 4) of the TMEM59L gene. This alteration results from a C to A substitution at nucleotide position 453, causing the aspartic acid (D) at amino acid position 151 to be replaced by a glutamic acid (E). 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	Benign	0.22
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.61
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.51	.;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.72	D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.22	.;N
REVEL	Benign	0.049
Sift	Benign	1.0	.;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0040	B;B
Vest4		0.072
MutPred		0.27		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.088
MPC		0.33
ClinPred		0.12	T
GERP RS		-1.2
Varity_R		0.064

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18726829;