10-61410488-G-A

Variant names:

• chr10-61410488-G-A
• rs1161404314
• NM_178505.8:c.941C>T

Variant summary

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

The NM_178505.8(TMEM26):​c.941C>T​(p.Ser314Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TMEM26 NM_178505.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22

Genes affected

TMEM26 (HGNC:28550): (transmembrane protein 26) This gene encodes a protein containing multiple transmembrane helices. It is a selective surface protein marker of brite/beige adipocytes, which may coexist with classical brown adipocytes in brown adipose tissue. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2015]

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=0.12963578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM26	NM_178505.8	c.941C>T	p.Ser314Leu	missense_variant	Exon 6 of 6	ENST00000399298.8	NP_848600.2
TMEM26	NR_134507.2	n.1241C>T		non_coding_transcript_exon_variant	Exon 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM26	ENST00000399298.8	c.941C>T	p.Ser314Leu	missense_variant	Exon 6 of 6	1	NM_178505.8	ENSP00000382237.3
TMEM26	ENST00000503886.5	n.941C>T		non_coding_transcript_exon_variant	Exon 6 of 7	2		ENSP00000425286.1
TMEM26	ENST00000507507.1	n.1301C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.941C>T (p.S314L) alteration is located in exon 6 (coding exon 6) of the TMEM26 gene. This alteration results from a C to T substitution at nucleotide position 941, causing the serine (S) at amino acid position 314 to be replaced by a leucine (L). 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	Benign	0.13
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.078
Sift	Benign	0.091	T
Sift4G	Benign	0.19	T
Polyphen		0.18	B
Vest4		0.23
MutPred		0.37		Loss of disorder (P = 0.0124);
MVP		0.15
MPC		0.31
ClinPred		0.30	T
GERP RS		3.9
Varity_R		0.046
gMVP		0.43

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: rs1161404314; hg19: chr10-63170246;