rs17256042

Positions:

• chr7-150793150-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001101312.2(TMEM176B):​c.538C>T​(p.Arg180Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0426 in 1,614,104 control chromosomes in the GnomAD database, including 1,673 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.033 (102 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1571 hom.)
• Consequence: TMEM176B NM_001101312.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.235

Genes affected

TMEM176B (HGNC:29596): (transmembrane protein 176B) Predicted to be involved in negative regulation of dendritic cell differentiation. Predicted to be located in nuclear membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002884835).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM176B	NM_001101312.2	c.538C>T	p.Arg180Trp	missense_variant	5/7	ENST00000326442.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM176B	ENST00000326442.10	c.538C>T	p.Arg180Trp	missense_variant	5/7	1	NM_001101312.2	P1

Frequencies

GnomAD3 genomes AF: 0.0331 AC: 5038 AN: 152140 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0505

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0330 AC: 8294 AN: 251370 Hom.: 171 AF XY: 0.0328 AC XY: 4457 AN XY: 135860

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.0224

Gnomad ASJ exome AF: 0.0405

Gnomad EAS exome AF: 0.00217

Gnomad SAS exome AF: 0.0109

Gnomad FIN exome AF: 0.0306

Gnomad NFE exome AF: 0.0500

Gnomad OTH exome AF: 0.0373

GnomAD4 exome AF: 0.0436 AC: 63718 AN: 1461846 Hom.: 1571 Cov.: 32 AF XY: 0.0430 AC XY: 31259 AN XY: 727222

Gnomad4 AFR exome AF: 0.0100

Gnomad4 AMR exome AF: 0.0226

Gnomad4 ASJ exome AF: 0.0391

Gnomad4 EAS exome AF: 0.00116

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.0313

Gnomad4 NFE exome AF: 0.0504

Gnomad4 OTH exome AF: 0.0391

GnomAD4 genome AF: 0.0331 AC: 5033 AN: 152258 Hom.: 102 Cov.: 32 AF XY: 0.0318 AC XY: 2368 AN XY: 74432

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.0325

Gnomad4 ASJ AF: 0.0386

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.0290

Gnomad4 NFE AF: 0.0505

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0462 Hom.: 445

Bravo AF: 0.0321

TwinsUK AF: 0.0518 AC: 192

ALSPAC AF: 0.0509 AC: 196

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.0533 AC: 458

ExAC AF: 0.0329 AC: 3996

Asia WGS AF: 0.00664 AC: 24 AN: 3478

EpiCase AF: 0.0500

EpiControl AF: 0.0522

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.047	T;T;T;T;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.013	N
MetaRNN	Benign	0.0029	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N
REVEL	Benign	0.082
Sift	Benign	0.073	T;T;T;T;T;T
Sift4G	Uncertain	0.013	D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;D;.
Vest4		0.14
MPC		0.19
ClinPred		0.022	T
GERP RS		-2.4
Varity_R		0.049
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs17256042; hg19: chr7-150490238;