10-49167938-G-A

Position:

• chr10-49167938-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001288740.3(TMEM273):​c.68C>T​(p.Ala23Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TMEM273 NM_001288740.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

Genes affected

TMEM273 (HGNC:27274): (transmembrane protein 273) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15774363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM273	NM_001288740.3	c.68C>T	p.Ala23Val	missense_variant	2/7	ENST00000374153.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM273	ENST00000374153.7	c.68C>T	p.Ala23Val	missense_variant	2/7	3	NM_001288740.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome Cov.: 33

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

Jul 13, 2021

The c.68C>T (p.A23V) alteration is located in exon 2 (coding exon 2) of the C10orf128 gene. This alteration results from a C to T substitution at nucleotide position 68, causing the alanine (A) at amino acid position 23 to be replaced by a valine (V). 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	Uncertain	0.52
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;.;T;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.84	T;T;T;T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Uncertain	-3.6	.;D;D;D;D
REVEL	Benign	0.029
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.41, 0.077, 0.58	.;B;B;.;P
Vest4		0.36
MutPred		0.34		.;Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);.;Gain of sheet (P = 0.0344);
MVP		0.36
MPC		0.15
ClinPred		0.96	D
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1846304414; hg19: chr10-50375983;