7-150804851-G-A

Variant names:

• chr7-150804851-G-A
• NM_018487.3:c.691G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018487.3(TMEM176A):​c.691G>A​(p.Glu231Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM176A NM_018487.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.454

Genes affected

TMEM176A (HGNC:24930): (transmembrane protein 176A) Predicted to be involved in negative regulation of dendritic cell differentiation. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07272309).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM176A	NM_018487.3	c.691G>A	p.Glu231Lys	missense_variant	Exon 7 of 7	ENST00000004103.8	NP_060957.2
TMEM176A	XM_011516376.4	c.742G>A	p.Glu248Lys	missense_variant	Exon 7 of 7		XP_011514678.1
TMEM176A	XM_011516378.3	c.631G>A	p.Glu211Lys	missense_variant	Exon 6 of 6		XP_011514680.1
TMEM176A	XM_024446824.2	c.580G>A	p.Glu194Lys	missense_variant	Exon 6 of 6		XP_024302592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM176A	ENST00000004103.8	c.691G>A	p.Glu231Lys	missense_variant	Exon 7 of 7	1	NM_018487.3	ENSP00000004103.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.691G>A (p.E231K) alteration is located in exon 7 (coding exon 6) of the TMEM176A gene. This alteration results from a G to A substitution at nucleotide position 691, causing the glutamic acid (E) at amino acid position 231 to be replaced by a lysine (K). 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	0.095
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.1
DANN	Benign	0.89
DEOGEN2	Benign	0.0032	T;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.43	.;T;.;T
M_CAP	Benign	0.00073	T
MetaRNN	Benign	0.073	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.090	N;N;N;.
REVEL	Benign	0.10
Sift	Benign	0.24	T;T;T;.
Sift4G	Benign	0.20	T;T;T;.
Polyphen		0.035	B;B;.;.
Vest4		0.025
MutPred		0.39		Gain of MoRF binding (P = 0.0029);Gain of MoRF binding (P = 0.0029);.;.;
MVP		0.12
MPC		0.38
ClinPred		0.13	T
GERP RS		0.94
Varity_R		0.052
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-150501939;