7-131504449-C-T

Position:

• chr7-131504449-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001018111.3(PODXL):​c.1539G>A​(p.Leu513=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,613,732 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (12 hom.)
• Consequence: PODXL NM_001018111.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.15

Genes affected

PODXL (HGNC:9171): (podocalyxin like) This gene encodes a member of the sialomucin protein family. The encoded protein was originally identified as an important component of glomerular podocytes. Podocytes are highly differentiated epithelial cells with interdigitating foot processes covering the outer aspect of the glomerular basement membrane. Other biological activities of the encoded protein include: binding in a membrane protein complex with Na+/H+ exchanger regulatory factor to intracellular cytoskeletal elements, playing a role in hematopoetic cell differentiation, and being expressed in vascular endothelium cells and binding to L-selectin. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 7-131504449-C-T is Benign according to our data. Variant chr7-131504449-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 790357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.15 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PODXL	NM_001018111.3	c.1539G>A	p.Leu513=	synonymous_variant	9/9	ENST00000378555.8
PODXL	NM_005397.4	c.1443G>A	p.Leu481=	synonymous_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PODXL	ENST00000378555.8	c.1539G>A	p.Leu513=	synonymous_variant	9/9	1	NM_001018111.3	P2
PODXL	ENST00000322985.9	c.1443G>A	p.Leu481=	synonymous_variant	8/8	1		A2
PODXL	ENST00000484346.1	n.298G>A		non_coding_transcript_exon_variant	2/2	2
PODXL	ENST00000446198.5	c.*804G>A		3_prime_UTR_variant, NMD_transcript_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 456 AN: 152240 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00376

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00249 AC: 627 AN: 251474 Hom.: 0 AF XY: 0.00269 AC XY: 366 AN XY: 135910

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00610

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00318 AC: 4647 AN: 1461374 Hom.: 12 Cov.: 31 AF XY: 0.00318 AC XY: 2313 AN XY: 727024

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00588

Gnomad4 NFE exome AF: 0.00363

Gnomad4 OTH exome AF: 0.00272

GnomAD4 genome AF: 0.00299 AC: 456 AN: 152358 Hom.: 4 Cov.: 32 AF XY: 0.00317 AC XY: 236 AN XY: 74512

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00800

Gnomad4 NFE AF: 0.00376

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00256 Hom.: 1

Bravo AF: 0.00247

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00332

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PODXL: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

PODXL-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.0
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150526057; hg19: chr7-131189208;