15-42211714-C-T

Variant summary

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

The NM_015497.5(TMEM87A):c.1662G>A(p.Met554Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM87A NM_015497.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.41

Genes affected

TMEM87A (HGNC:24522): (transmembrane protein 87A) Involved in retrograde transport, endosome to Golgi. Located in Golgi cisterna membrane. [provided by Alliance of Genome Resources, Apr 2022]

VPS39-DT (HGNC:55378): (VPS39 divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM87A	NM_015497.5	c.1662G>A	p.Met554Ile	missense_variant	20/20	ENST00000389834.9
VPS39-DT	XR_932181.3	n.438+2797C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM87A	ENST00000389834.9	c.1662G>A	p.Met554Ile	missense_variant	20/20	2	NM_015497.5	P4
VPS39-DT	ENST00000563846.5	n.426+2797C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Aug 13, 2021

The c.1662G>A (p.M554I) alteration is located in exon 20 (coding exon 20) of the TMEM87A gene. This alteration results from a G to A substitution at nucleotide position 1662, causing the methionine (M) at amino acid position 554 to be replaced by an isoleucine (I). 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.0081	T
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.029	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		0.98	.;D
Vest4		0.66
MutPred		0.25		.;Loss of disorder (P = 0.1459);
MVP		0.24
MPC		0.98
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2050290814; hg19: chr15-42503912;