2-96254112-A-T

Variant names:

• chr2-96254112-A-T
• rs772714957
• NM_017849.4:c.413T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_017849.4(TMEM127):​c.413T>A​(p.Leu138Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.75

Genes affected

TMEM127 (HGNC:26038): (transmembrane protein 127) This gene encodes a transmembrane protein with four predicted transmembrane domains. The protein is associated with a subpopulation of vesicular organelles corresponding to early endosomal structures, with the Golgi, and with lysosomes, and may participate in protein trafficking between these structures. Mutations in this gene and several other genes cause pheochromocytomas. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Aug 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Transmembrane protein 127 (size 237) in uniprot entity TM127_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_017849.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.413T>A	p.Leu138Gln	missense_variant	Exon 4 of 4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.413T>A	p.Leu138Gln	missense_variant	Exon 4 of 4		NP_001180233.1
TMEM127	NM_001407282.1	c.161T>A	p.Leu54Gln	missense_variant	Exon 3 of 3		NP_001394211.1
TMEM127	NM_001407283.1	c.161T>A	p.Leu54Gln	missense_variant	Exon 3 of 3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.413T>A	p.Leu138Gln	missense_variant	Exon 4 of 4	1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.413T>A	p.Leu138Gln	missense_variant	Exon 4 of 4	1		ENSP00000416660.1
TMEM127	ENST00000435268.1	c.161T>A	p.Leu54Gln	missense_variant	Exon 3 of 3	3		ENSP00000411810.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	36
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	2.0	M;M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Pathogenic	0.74
Sift	Benign	0.075	T;T;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.87
MutPred		0.42		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);.;
MVP		0.93
MPC		1.3
ClinPred		0.97	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.81		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs772714957; hg19: chr2-96919850;