7-75988501-G-T

Position:

• chr7-75988501-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031925.3(TMEM120A):​c.393C>A​(p.Asp131Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,714 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: TMEM120A NM_031925.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.283

Genes affected

TMEM120A (HGNC:21697): (transmembrane protein 120A) Predicted to enable ion channel activity. Involved in fat cell differentiation; protein heterooligomerization; and protein homooligomerization. Predicted to be located in plasma membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM120A	NM_031925.3	c.393C>A	p.Asp131Glu	missense_variant	5/12	ENST00000493111.7	NP_114131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM120A	ENST00000493111.7	c.393C>A	p.Asp131Glu	missense_variant	5/12	1	NM_031925.3	ENSP00000473983.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248120 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135124

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: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459714 Hom.: 0 Cov.: 34 AF XY: 0.00000689 AC XY: 5 AN XY: 726138

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: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 28

ExAC AF: 0.0000166 AC: 2

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

Nov 14, 2023

The c.393C>A (p.D131E) alteration is located in exon 5 (coding exon 5) of the TMEM120A gene. This alteration results from a C to A substitution at nucleotide position 393, causing the aspartic acid (D) at amino acid position 131 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	Pathogenic	0.79
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.073	T;T;.;.;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;.;D;D;D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MutationAssessor	Uncertain	2.0	M;.;.;.;.
PrimateAI	Pathogenic	0.87	D
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		0.80	P;.;.;.;.
Vest4		0.52
MVP		0.081
GERP RS		1.5
Varity_R		0.067
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs140919124; hg19: chr7-75617819;