chr7-150793095-A-G

Variant names:

• chr7-150793095-A-G
• rs1300336890
• NM_001101312.2:c.593T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001101312.2(TMEM176B):​c.593T>C​(p.Met198Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM176B NM_001101312.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM176B	NM_001101312.2	c.593T>C	p.Met198Thr	missense_variant	Exon 5 of 7	ENST00000326442.10	NP_001094782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM176B	ENST00000326442.10	c.593T>C	p.Met198Thr	missense_variant	Exon 5 of 7	1	NM_001101312.2	ENSP00000318409.5

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151900 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 6.84e-7 AC: 1 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151900 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74190

African (AFR) AF: 0.000169 AC: 7 AN: 41342

American (AMR) AF: 0.00 AC: 0 AN: 15244

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.593T>C (p.M198T) alteration is located in exon 5 (coding exon 4) of the TMEM176B gene. This alteration results from a T to C substitution at nucleotide position 593, causing the methionine (M) at amino acid position 198 to be replaced by a threonine (T). 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	Benign	0.29
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.20	T;T;T;T;T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.47	.;.;.;T;.;T
M_CAP	Benign	0.0076	T
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;L;L;L;.
PhyloP100		1.3
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D
REVEL	Benign	0.071
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		0.89	P;P;P;P;P;.
Vest4		0.50
MutPred		0.82		Loss of MoRF binding (P = 0.0916);Loss of MoRF binding (P = 0.0916);Loss of MoRF binding (P = 0.0916);Loss of MoRF binding (P = 0.0916);Loss of MoRF binding (P = 0.0916);.;
MVP		0.14
MPC		0.19
ClinPred		0.50	D
GERP RS		2.5
Varity_R		0.54
gMVP		0.41
Mutation Taster		=94/6	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: rs1300336890; hg19: chr7-150490183;