19-46493967-T-C

Variant names:

• chr19-46493967-T-C
• rs751952034
• NM_020709.3:c.1499A>G

Variant summary

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

The NM_020709.3(PNMA8B):​c.1499A>G​(p.Asn500Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PNMA8B NM_020709.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.374

Genes affected

PNMA8B (HGNC:29206): (PNMA family member 8B)

PPP5D1P (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=0.041146517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMA8B	NM_020709.3	c.1499A>G	p.Asn500Ser	missense_variant	Exon 1 of 1	ENST00000599531.2	NP_065760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNMA8B	ENST00000599531.2	c.1499A>G	p.Asn500Ser	missense_variant	Exon 1 of 1	6	NM_020709.3	ENSP00000473036.1
PNMA8B	ENST00000594749.1	n.165+1748A>G		intron_variant	Intron 1 of 1	5
PPP5D1P	ENST00000602017.7	n.378-12527A>G		intron_variant	Intron 3 of 3	3
PPP5D1P	ENST00000702671.1	n.394-12527A>G		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248846 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 135028

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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461150 Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3 AN XY: 726870

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1499A>G (p.N500S) alteration is located in exon 1 (coding exon 1) of the PNMAL2 gene. This alteration results from a A to G substitution at nucleotide position 1499, causing the asparagine (N) at amino acid position 500 to be replaced by a serine (S). 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	0.073
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.85
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.041	T
PrimateAI	Benign	0.30	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.037
MVP		0.14
GERP RS		0.60
Varity_R		0.062
gMVP		0.023

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

LitVar

Other links and lift over

dbSNP: rs751952034; hg19: chr19-46997224;