rs3212298

Positions:

• chr7-131508980-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001018111.3(PODXL):​c.1072G>A​(p.Val358Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0514 in 1,613,412 control chromosomes in the GnomAD database, including 3,201 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.044 (258 hom., cov: 31)
  • Exomes 𝑓: 0.052 (2943 hom.)
• Consequence: PODXL NM_001018111.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.88

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010284156).
• BP6: Variant 7-131508980-C-T is Benign according to our data. Variant chr7-131508980-C-T is described in ClinVar as [Benign]. Clinvar id is 1236309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-131508980-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PODXL	NM_001018111.3	c.1072G>A	p.Val358Ile	missense_variant	5/9	ENST00000378555.8
PODXL	NM_005397.4	c.976G>A	p.Val326Ile	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PODXL	ENST00000378555.8	c.1072G>A	p.Val358Ile	missense_variant	5/9	1	NM_001018111.3	P2
PODXL	ENST00000322985.9	c.976G>A	p.Val326Ile	missense_variant	4/8	1		A2
PODXL	ENST00000487965.1	n.423G>A		non_coding_transcript_exon_variant	1/4	2
PODXL	ENST00000446198.5	c.*337G>A		3_prime_UTR_variant, NMD_transcript_variant	3/7	2

Frequencies

GnomAD3 genomes AF: 0.0444 AC: 6752 AN: 152114 Hom.: 258 Cov.: 31

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0542

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0463

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0455

Gnomad OTH AF: 0.0488

GnomAD3 exomes AF: 0.0628 AC: 15795 AN: 251452 Hom.: 913 AF XY: 0.0654 AC XY: 8886 AN XY: 135902

Gnomad AFR exome AF: 0.0162

Gnomad AMR exome AF: 0.0248

Gnomad ASJ exome AF: 0.0533

Gnomad EAS exome AF: 0.240

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.0448

Gnomad NFE exome AF: 0.0456

Gnomad OTH exome AF: 0.0550

GnomAD4 exome AF: 0.0522 AC: 76244 AN: 1461180 Hom.: 2943 Cov.: 31 AF XY: 0.0540 AC XY: 39256 AN XY: 726958

Gnomad4 AFR exome AF: 0.0146

Gnomad4 AMR exome AF: 0.0250

Gnomad4 ASJ exome AF: 0.0556

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.0443

Gnomad4 NFE exome AF: 0.0445

Gnomad4 OTH exome AF: 0.0582

GnomAD4 genome AF: 0.0443 AC: 6746 AN: 152232 Hom.: 258 Cov.: 31 AF XY: 0.0467 AC XY: 3475 AN XY: 74414

Gnomad4 AFR AF: 0.0168

Gnomad4 AMR AF: 0.0251

Gnomad4 ASJ AF: 0.0542

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.0463

Gnomad4 NFE AF: 0.0455

Gnomad4 OTH AF: 0.0482

Alfa AF: 0.0494 Hom.: 599

Bravo AF: 0.0420

TwinsUK AF: 0.0453 AC: 168

ALSPAC AF: 0.0496 AC: 191

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.0472 AC: 406

ExAC AF: 0.0637 AC: 7729

Asia WGS AF: 0.130 AC: 452 AN: 3478

EpiCase AF: 0.0447

EpiControl AF: 0.0463

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

PODXL-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

This variant is classified as 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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0020
DANN	Benign	0.20
DEOGEN2	Benign	0.083	T;.
Eigen	Benign	-2.6
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.28	T;T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.84	N;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.44	N;N
REVEL	Benign	0.010
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.013
MPC		0.19
ClinPred		0.0012	T
GERP RS		-7.7
Varity_R		0.017
gMVP		0.11

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: rs3212298; hg19: chr7-131193739; COSMIC: COSV59869153; COSMIC: COSV59869153;