NM_001146685.2:c.401G>C

Variant names:

• chr1-1427696-G-C
• rs1317865800
• NM_001146685.2:c.401G>C

Variant summary

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

The NM_001146685.2(TMEM278):​c.401G>C​(p.Arg134Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000846 in 1,181,970 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R134H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 18)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: TMEM278 NM_001146685.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0310
• 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.401G>C	p.Arg134Pro	missense	Exon 2 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.401G>C	p.Arg134Pro	missense	Exon 2 of 2	ENSP00000455099.1	A6NKF7

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome AF: 8.46e-7 AC: 1 AN: 1181970 Hom.: 0 Cov.: 34 AF XY: 0.00000173 AC XY: 1 AN XY: 578072

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23804

American (AMR) AF: 0.00 AC: 0 AN: 15796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18034

East Asian (EAS) AF: 0.00 AC: 0 AN: 25652

South Asian (SAS) AF: 0.00 AC: 0 AN: 47974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3374

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 973452

Other (OTH) AF: 0.00 AC: 0 AN: 47044

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 18

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.47	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.031
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.7	D
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.060	T
Polyphen		0.99	D
Vest4		0.45
MVP		0.57
GERP RS		1.7
Varity_R		0.43
gMVP		0.18
Mutation Taster		=88/12	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: rs1317865800; hg19: chr1-1363076;