16-372614-C-T

Variant names:

• chr16-372614-C-T
• NM_021259.3:c.2016G>A

Variant summary

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

The NM_021259.3(PGAP6):​c.2016G>A​(p.Met672Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,572 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: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PGAP6 NM_021259.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.372

Genes affected

PGAP6 (HGNC:17205): (post-GPI attachment to proteins 6) Predicted to enable phospholipase A2 activity. Located in extracellular exosome and lysosomal 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=0.24471775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAP6	NM_021259.3	c.2016G>A	p.Met672Ile	missense_variant	Exon 12 of 13	ENST00000431232.7	NP_067082.2
PGAP6	XM_047434413.1	c.1437G>A	p.Met479Ile	missense_variant	Exon 13 of 14		XP_047290369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAP6	ENST00000431232.7	c.2016G>A	p.Met672Ile	missense_variant	Exon 12 of 13	1	NM_021259.3	ENSP00000401338.2
PGAP6	ENST00000250930.7	c.1437G>A	p.Met479Ile	missense_variant	Exon 12 of 13	2		ENSP00000250930.3
PGAP6	ENST00000448854.1	c.660G>A	p.Met220Ile	missense_variant	Exon 5 of 5	2		ENSP00000401931.1
PGAP6	ENST00000424078.5	c.421-331G>A		intron_variant	Intron 3 of 3	3		ENSP00000397620.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458572 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725678

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2016G>A (p.M672I) alteration is located in exon 12 (coding exon 12) of the TMEM8A gene. This alteration results from a G to A substitution at nucleotide position 2016, causing the methionine (M) at amino acid position 672 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.047	D;D;T
Sift4G	Uncertain	0.026	D;D;T
Polyphen		0.96	D;.;.
Vest4		0.52
MutPred		0.44		Gain of glycosylation at S671 (P = 0.0554);.;.;
MVP		0.26
MPC		0.28
ClinPred		0.82	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.093
gMVP		0.43

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: chr16-422614;