NM_144626.3:c.47C>G

Variant names:

• chr1-43272769-C-G
• rs1471313634
• NM_144626.3:c.47C>G

Variant summary

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

The NM_144626.3(TMEM125):​c.47C>G​(p.Pro16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000131 in 1,525,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P16S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: TMEM125 NM_144626.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.453
• Publications: 0 publications found

Genes affected

TMEM125 (HGNC:28275): (transmembrane protein 125) Predicted to be integral component of 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=0.036185265).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144626.3. 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
	TMEM125	NM_144626.3	MANE Select	c.47C>G	p.Pro16Arg	missense	Exon 4 of 4	NP_653227.1	Q96AQ2
	TMEM125	NM_001320244.2		c.47C>G	p.Pro16Arg	missense	Exon 4 of 4	NP_001307173.1	Q96AQ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM125	ENST00000439858.6	TSL:2 MANE Select	c.47C>G	p.Pro16Arg	missense	Exon 4 of 4	ENSP00000429775.1	Q96AQ2
	TMEM125	ENST00000432792.6	TSL:1	c.47C>G	p.Pro16Arg	missense	Exon 4 of 4	ENSP00000429275.1	Q96AQ2
	TMEM125	ENST00000908432.1		c.47C>G	p.Pro16Arg	missense	Exon 3 of 3	ENSP00000578491.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1373398 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 673188

African (AFR) AF: 0.00 AC: 0 AN: 30934

American (AMR) AF: 0.00 AC: 0 AN: 32858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21120

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38306

South Asian (SAS) AF: 0.00 AC: 0 AN: 72692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4340

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068008

Other (OTH) AF: 0.00 AC: 0 AN: 56374

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

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

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Benign	0.078
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.7
DANN	Benign	0.87
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L
PhyloP100		0.45
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.027
Sift	Benign	0.56	T
Sift4G	Benign	0.85	T
Polyphen		0.0030	B
Vest4		0.12
MutPred		0.21		Loss of loop (P = 0.0153)
MVP		0.32
MPC		0.23
ClinPred		0.046	T
GERP RS		1.6
Varity_R		0.039
gMVP		0.36
Mutation Taster		=90/10	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: rs1471313634; hg19: chr1-43738440;