2-96254835-G-C

Position:

• chr2-96254835-G-C

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.407C>G​(p.Thr136Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T136T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM127 NM_017849.4 missense, splice_region
• Scores: Splicing: ADA: 0.9397
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.50

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: MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.407C>G	p.Thr136Arg	missense_variant, splice_region_variant	3/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.407C>G	p.Thr136Arg	missense_variant, splice_region_variant	3/4		NP_001180233.1
TMEM127	NM_001407282.1	c.155C>G	p.Thr52Arg	missense_variant, splice_region_variant	2/3		NP_001394211.1
TMEM127	NM_001407283.1	c.155C>G	p.Thr52Arg	missense_variant, splice_region_variant	2/3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.407C>G	p.Thr136Arg	missense_variant, splice_region_variant	3/4	1	NM_017849.4	ENSP00000258439	P1
TMEM127	ENST00000432959.1	c.407C>G	p.Thr136Arg	missense_variant, splice_region_variant	3/4	1		ENSP00000416660	P1
TMEM127	ENST00000435268.1	c.155C>G	p.Thr52Arg	missense_variant, splice_region_variant	2/3	3		ENSP00000411810

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461780 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.97	D;D;.
Vest4		0.98
MutPred		0.71		Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);.;
MVP		0.81
MPC		1.3
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.60
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-96920573;