2-96253904-C-T

Variant names:

• chr2-96253904-C-T
• rs3852673
• NM_017849.4:c.621G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017849.4(TMEM127):​c.621G>A​(p.Ala207Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,613,928 control chromosomes in the GnomAD database, including 25,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A207A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1782 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23773 hom.)
• Consequence: TMEM127 NM_017849.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.45
• Publications: 20 publications found

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]

TMEM127 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-96253904-C-T is Benign according to our data. Variant chr2-96253904-C-T is described in ClinVar as Benign. ClinVar VariationId is 45824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017849.4. 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
	TMEM127	NM_017849.4	MANE Select	c.621G>A	p.Ala207Ala	synonymous	Exon 4 of 4	NP_060319.1	O75204
	TMEM127	NM_001193304.3		c.621G>A	p.Ala207Ala	synonymous	Exon 4 of 4	NP_001180233.1	O75204
	TMEM127	NM_001407282.1		c.369G>A	p.Ala123Ala	synonymous	Exon 3 of 3	NP_001394211.1	C9J4H2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM127	ENST00000258439.8	TSL:1 MANE Select	c.621G>A	p.Ala207Ala	synonymous	Exon 4 of 4	ENSP00000258439.3	O75204
	TMEM127	ENST00000432959.2	TSL:1	c.621G>A	p.Ala207Ala	synonymous	Exon 4 of 4	ENSP00000416660.1	O75204
	TMEM127	ENST00000910913.1		c.621G>A	p.Ala207Ala	synonymous	Exon 3 of 3	ENSP00000580972.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21620 AN: 151974 Hom.: 1777 Cov.: 32

Gnomad AFR AF: 0.0640

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.0828

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.181

GnomAD2 exomes AF: 0.163 AC: 40976 AN: 251306 AF XY: 0.171

Gnomad AFR exome AF: 0.0601

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.0758

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.174 AC: 254700 AN: 1461836 Hom.: 23773 Cov.: 33 AF XY: 0.178 AC XY: 129721 AN XY: 727206

African (AFR) AF: 0.0650 AC: 2175 AN: 33480

American (AMR) AF: 0.126 AC: 5635 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 4673 AN: 26136

East Asian (EAS) AF: 0.0827 AC: 3285 AN: 39698

South Asian (SAS) AF: 0.276 AC: 23781 AN: 86258

European-Finnish (FIN) AF: 0.150 AC: 8033 AN: 53412

Middle Eastern (MID) AF: 0.255 AC: 1471 AN: 5768

European-Non Finnish (NFE) AF: 0.175 AC: 194782 AN: 1111972

Other (OTH) AF: 0.180 AC: 10865 AN: 60394

GnomAD4 genome AF: 0.142 AC: 21644 AN: 152092 Hom.: 1782 Cov.: 32 AF XY: 0.145 AC XY: 10765 AN XY: 74374

African (AFR) AF: 0.0642 AC: 2665 AN: 41512

American (AMR) AF: 0.161 AC: 2453 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 622 AN: 3468

East Asian (EAS) AF: 0.0824 AC: 426 AN: 5168

South Asian (SAS) AF: 0.270 AC: 1297 AN: 4812

European-Finnish (FIN) AF: 0.145 AC: 1535 AN: 10588

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12062 AN: 67946

Other (OTH) AF: 0.183 AC: 386 AN: 2110

Alfa AF: 0.166 Hom.: 3376

Bravo AF: 0.133

Asia WGS AF: 0.173 AC: 601 AN: 3478

EpiCase AF: 0.186

EpiControl AF: 0.181

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Pheochromocytoma (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary pheochromocytoma-paraganglioma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.19
DANN	Benign	0.69
PhyloP100		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs3852673; hg19: chr2-96919642; COSMIC: COSV51497428;