1-53069856-A-G

Position:

• chr1-53069856-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_153703.5(PODN):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PODN NM_153703.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.859

Genes affected

PODN (HGNC:23174): (podocan) The protein encoded by this gene is a member of the small leucine-rich repeat protein family and contains an amino terminal CX3CXCX7C cysteine-rich cluster followed by a leucine-rich repeat domain. Studies suggest that this protein could function to inhibit smooth muscle cell proliferation and migration following arterial injury. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PODN	NM_153703.5	c.1A>G	p.Met1?	start_lost	2/11	ENST00000312553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PODN	ENST00000312553.10	c.1A>G	p.Met1?	start_lost	2/11	1	NM_153703.5	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1422494 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 704282

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.: 33

Bravo AF: 0.0000113

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

Feb 13, 2024

The c.145A>G (p.M49V) alteration is located in exon 2 (coding exon 2) of the PODN gene. This alteration results from a A to G substitution at nucleotide position 145, causing the methionine (M) at amino acid position 49 to be replaced by a valine (V). 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
BayesDel_addAF	Benign	-0.0051	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.52	T;.;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.88	N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.23	N;N;.;N
REVEL	Benign	0.24
Sift	Uncertain	0.016	D;D;.;D
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.021	B;B;B;B
Vest4		0.38
MutPred		0.18		.;Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;
MVP		0.62
MPC		0.83
ClinPred		0.93	D
GERP RS		4.2
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1644087149; hg19: chr1-53535528;