NM_001146685.2:c.254C>T

Variant names:

• chr1-1426381-C-T
• rs373580371
• NM_001146685.2:c.254C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001146685.2(TMEM278):​c.254C>T​(p.Ser85Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000032 in 1,251,598 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: TMEM278 NM_001146685.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.983
• Publications: 0 publications found

Genes affected

TMEM278 (HGNC:37099): (transmembrane protein 88B) Predicted to enable PDZ domain binding activity. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146685.2. 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
	TMEM278	NM_001146685.2	MANE Select	c.254C>T	p.Ser85Leu	missense	Exon 1 of 2	NP_001140157.1	A6NKF7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM88B	ENST00000378821.4	TSL:2 MANE Select	c.254C>T	p.Ser85Leu	missense	Exon 1 of 2	ENSP00000455099.1	A6NKF7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 31524 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000320 AC: 4 AN: 1251598 Hom.: 0 Cov.: 33 AF XY: 0.00000658 AC XY: 4 AN XY: 607910

African (AFR) AF: 0.00 AC: 0 AN: 25042

American (AMR) AF: 0.0000549 AC: 1 AN: 18208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18024

East Asian (EAS) AF: 0.00 AC: 0 AN: 29910

South Asian (SAS) AF: 0.0000165 AC: 1 AN: 60620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3488

European-Non Finnish (NFE) AF: 0.00000198 AC: 2 AN: 1008312

Other (OTH) AF: 0.00 AC: 0 AN: 51472

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.54	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.98
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.8	D
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.62
MVP		0.76
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.42
gMVP		0.22
Mutation Taster		=86/14	polymorphism

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: rs373580371; hg19: chr1-1361761; COSMIC: COSV104700533; COSMIC: COSV104700533;