7-75987756-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_031925.3(TMEM120A):c.746G>A(p.Arg249Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000295 in 1,612,198 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00097 (10 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: TMEM120A NM_031925.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.06

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01767397).
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM120A	NM_031925.3	c.746G>A	p.Arg249Gln	missense_variant	9/12	ENST00000493111.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM120A	ENST00000493111.7	c.746G>A	p.Arg249Gln	missense_variant	9/12	1	NM_031925.3	P1

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152234 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000106 AC: 26 AN: 245624 Hom.: 0 AF XY: 0.000119 AC XY: 16 AN XY: 134274

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000217

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000225 AC: 329 AN: 1459964 Hom.: 1 Cov.: 38 AF XY: 0.000216 AC XY: 157 AN XY: 726252

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000281

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000966 AC: 147 AN: 152234 Hom.: 10 Cov.: 31 AF XY: 0.000861 AC XY: 64 AN XY: 74368

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000297 Hom.: 0

Bravo AF: 0.00132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000361 AC: 3

ExAC AF: 0.0000834 AC: 10

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

Oct 22, 2021

The c.746G>A (p.R249Q) alteration is located in exon 9 (coding exon 9) of the TMEM120A gene. This alteration results from a G to A substitution at nucleotide position 746, causing the arginine (R) at amino acid position 249 to be replaced by a glutamine (Q). 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	0.88
BayesDel_addAF	Benign	-0.00054	T
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	29
Dann	Benign	0.82
DEOGEN2	Benign	0.16	T;.;.
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.018	T;T;T
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Uncertain	0.70	T
Sift4G	Uncertain	0.011	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.78
MVP		0.14
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.086
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs201249328; hg19: chr7-75617074; COSMIC: COSV58693610; COSMIC: COSV58693610;