7-150792157-G-T

Variant names:

• chr7-150792157-G-T
• rs139047290
• NM_001101312.2:c.619C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001101312.2(TMEM176B):​c.619C>A​(p.Arg207Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,613,592 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R207C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: TMEM176B NM_001101312.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.653
• Publications: 3 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1104292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM176B	NM_001101312.2	c.619C>A	p.Arg207Ser	missense_variant	Exon 6 of 7	ENST00000326442.10	NP_001094782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM176B	ENST00000326442.10	c.619C>A	p.Arg207Ser	missense_variant	Exon 6 of 7	1	NM_001101312.2	ENSP00000318409.5

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152142 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000278 AC: 70 AN: 251414 AF XY: 0.000368

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: 0.000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000179 AC: 261 AN: 1461450 Hom.: 1 Cov.: 31 AF XY: 0.000232 AC XY: 169 AN XY: 727030

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.0000447 AC: 2 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000881 AC: 76 AN: 86232

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53308

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.000150 AC: 167 AN: 1111806

Other (OTH) AF: 0.0000994 AC: 6 AN: 60374

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152142 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74330

African (AFR) AF: 0.0000483 AC: 2 AN: 41422

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000428 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.000321 AC: 39

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.619C>A (p.R207S) alteration is located in exon 6 (coding exon 5) of the TMEM176B gene. This alteration results from a C to A substitution at nucleotide position 619, causing the arginine (R) at amino acid position 207 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.8
DANN	Benign	0.81
DEOGEN2	Benign	0.059	T;T;T;T;T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.73	.;.;.;T;.;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L;L;L;L;L;.
PhyloP100		0.65
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N
REVEL	Benign	0.098
Sift	Benign	0.10	T;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T
Polyphen		0.91	P;P;P;P;P;.
Vest4		0.45
MVP		0.33
MPC		0.15
ClinPred		0.045	T
GERP RS		0.16
Varity_R		0.10
gMVP		0.33
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139047290; hg19: chr7-150489245;