1-1427599-C-G

Variant names:

• chr1-1427599-C-G
• rs1052025607
• NM_001146685.2:c.304C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001146685.2(TMEM278):​c.304C>G​(p.Arg102Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000851 in 1,175,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. 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. R102C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 14)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: TMEM278 NM_001146685.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053542346).

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.304C>G	p.Arg102Gly	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.304C>G	p.Arg102Gly	missense	Exon 2 of 2	ENSP00000455099.1	A6NKF7

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD4 exome AF: 8.51e-7 AC: 1 AN: 1175006 Hom.: 0 Cov.: 34 AF XY: 0.00000175 AC XY: 1 AN XY: 572684

⚠️ 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: 24428

American (AMR) AF: 0.00 AC: 0 AN: 17580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18712

East Asian (EAS) AF: 0.00 AC: 0 AN: 26270

South Asian (SAS) AF: 0.00 AC: 0 AN: 45008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3386

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 967196

Other (OTH) AF: 0.00 AC: 0 AN: 46752

⚠️ 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.: 14

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	10
DANN	Benign	0.58
DEOGEN2	Benign	0.0020	T
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.054	T
MutationAssessor	Benign	0.70	N
PhyloP100		-1.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.55	N
Sift	Benign	0.61	T
Sift4G	Benign	0.77	T
Polyphen		0.0040	B
Vest4		0.17
MVP		0.58
GERP RS		1.5
Varity_R		0.075
gMVP		0.11
Mutation Taster		=95/5	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: rs1052025607; hg19: chr1-1362979;