15-42273302-T-C

Position:

• chr15-42273302-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198141.3(GANC):​c.-1180T>C 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 1,461,858 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: -0.0210

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032305777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GANC	NM_198141.3	c.-1180T>C		5_prime_UTR_premature_start_codon_gain_variant	1/24	ENST00000318010.13	NP_937784.2
TMEM87A	NM_015497.5	c.97A>G	p.Thr33Ala	missense_variant	1/20	ENST00000389834.9	NP_056312.2
GANC	NM_198141.3	c.-1180T>C		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.-1180T>C		5_prime_UTR_premature_start_codon_gain_variant	1/24	1	NM_198141.3	ENSP00000326227.8
TMEM87A	ENST00000389834.9	c.97A>G	p.Thr33Ala	missense_variant	1/20	2	NM_015497.5	ENSP00000374484.4
TMEM87A	ENST00000566014.2	c.97A>G	p.Thr33Ala	missense_variant	1/20	5		ENSP00000457308.2
TMEM87A	ENST00000704760.1	c.97A>G	p.Thr33Ala	missense_variant	1/20			ENSP00000516026.1
TMEM87A	ENST00000704761.1	c.97A>G	p.Thr33Ala	missense_variant	1/20			ENSP00000516027.1
GANC	ENST00000318010	c.-1180T>C		5_prime_UTR_variant	1/24	1	NM_198141.3	ENSP00000326227.8
TMEM87A	ENST00000448392.6	n.97A>G		non_coding_transcript_exon_variant	1/19	1		ENSP00000405379.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727234

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: 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2024

The c.97A>G (p.T33A) alteration is located in exon 1 (coding exon 1) of the TMEM87A gene. This alteration results from a A to G substitution at nucleotide position 97, causing the threonine (T) at amino acid position 33 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	0.056
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.4
DANN	Benign	0.93
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.20	T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.032	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.028
Sift	Benign	0.97	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.0	B;B
Vest4		0.043
MutPred		0.28		Gain of helix (P = 0.005);Gain of helix (P = 0.005);
MVP		0.043
MPC		0.26
ClinPred		0.077	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.24

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-42565500;