15-42273298-A-G

Position:

• chr15-42273298-A-G

Variant summary

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

The NM_198141.3(GANC):​c.-1184A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GANC NM_198141.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

Genes affected

GANC (HGNC:4139): (glucosidase alpha, neutral C) Glycosyl hydrolase enzymes hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. This gene encodes a member of glycosyl hydrolases family 31. This enzyme hydrolyses terminal, non-reducing 1,4-linked alpha-D-glucose residues and releases alpha-D-glucose. This is a key enzyme in glycogen metabolism and its gene localizes to a chromosomal region (15q15) that is associated with susceptibility to diabetes. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2014]

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]

TMEM87A (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=0.086592406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GANC	NM_198141.3	c.-1184A>G		5_prime_UTR_premature_start_codon_gain_variant	1/24	ENST00000318010.13	NP_937784.2
TMEM87A	NM_015497.5	c.101T>C	p.Val34Ala	missense_variant	1/20	ENST00000389834.9	NP_056312.2
GANC	NM_198141.3	c.-1184A>G		5_prime_UTR_variant	1/24	ENST00000318010.13	NP_937784.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GANC	ENST00000318010	c.-1184A>G		5_prime_UTR_premature_start_codon_gain_variant	1/24	1	NM_198141.3	ENSP00000326227.8
TMEM87A	ENST00000389834.9	c.101T>C	p.Val34Ala	missense_variant	1/20	2	NM_015497.5	ENSP00000374484.4
TMEM87A	ENST00000566014.2	c.101T>C	p.Val34Ala	missense_variant	1/20	5		ENSP00000457308.2
TMEM87A	ENST00000704760.1	c.101T>C	p.Val34Ala	missense_variant	1/20			ENSP00000516026.1
TMEM87A	ENST00000704761.1	c.101T>C	p.Val34Ala	missense_variant	1/20			ENSP00000516027.1
GANC	ENST00000318010	c.-1184A>G		5_prime_UTR_variant	1/24	1	NM_198141.3	ENSP00000326227.8
TMEM87A	ENST00000448392.6	n.101T>C		non_coding_transcript_exon_variant	1/19	1		ENSP00000405379.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251250 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135850

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 AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727236

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Jul 25, 2023

The c.101T>C (p.V34A) alteration is located in exon 1 (coding exon 1) of the TMEM87A gene. This alteration results from a T to C substitution at nucleotide position 101, causing the valine (V) at amino acid position 34 to be replaced by an alanine (A). 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	0.064
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.017	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.010	N;N
REVEL	Benign	0.044
Sift	Benign	0.22	T;D
Sift4G	Benign	0.37	T;D
Polyphen		0.0	B;B
Vest4		0.16
MVP		0.043
MPC		0.32
ClinPred		0.21	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.054
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs374705120; hg19: chr15-42565496;