2-112064232-C-A

Position:

• chr2-112064232-C-A

Variant summary

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

The NM_032824.3(TMEM87B):​c.297C>A​(p.His99Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM87B NM_032824.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.228

Genes affected

TMEM87B (HGNC:25913): (transmembrane protein 87B) This gene encodes a protein that may interact with human papillomavirus type 18 E6 oncogene. The protein is also likely to be involved in endosome-to-trans-Golgi network retrograde transport. The gene is expressed in adult and fetal tissues, including brain and heart. This gene is a component of the 2q13 deletion syndrome. Mutations in this gene may be associated with congenital heart defects. [provided by RefSeq, Aug 2016]

TMEM87B (HGNC:):

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=0.11573231).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM87B	NM_032824.3	c.297C>A	p.His99Gln	missense_variant	3/19	ENST00000283206.9	NP_116213.1
TMEM87B	NM_001329914.2	c.297C>A	p.His99Gln	missense_variant	3/19		NP_001316843.1
TMEM87B	XM_005263827.3	c.297C>A	p.His99Gln	missense_variant	3/19		XP_005263884.1
TMEM87B	XR_923049.2	n.620C>A		non_coding_transcript_exon_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM87B	ENST00000283206.9	c.297C>A	p.His99Gln	missense_variant	3/19	2	NM_032824.3	ENSP00000283206.4
TMEM87B	ENST00000650799.2	c.297C>A	p.His99Gln	missense_variant	3/19			ENSP00000498298.2
TMEM87B	ENST00000452614.6	c.297C>A	p.His99Gln	missense_variant	3/18	1		ENSP00000393998.2
TMEM87B	ENST00000452029.1	n.169C>A		non_coding_transcript_exon_variant	3/6	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251330 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135848

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2024

The c.297C>A (p.H99Q) alteration is located in exon 3 (coding exon 3) of the TMEM87B gene. This alteration results from a C to A substitution at nucleotide position 297, causing the histidine (H) at amino acid position 99 to be replaced by a glutamine (Q). 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	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.073
Eigen_PC	Benign	-0.055
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.11
Sift	Benign	0.21	T
Sift4G	Benign	0.28	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.54		Gain of helix (P = 0.062);
MVP		0.22
MPC		0.12
ClinPred		0.13	T
GERP RS		1.4
Varity_R		0.11
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs573166820; hg19: chr2-112821809;