rs3735035

Positions:

• chr7-131511200-C-T

Variant summary

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

The ENST00000378555.8(PODXL):​c.334G>A​(p.Gly112Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 1,613,396 control chromosomes in the GnomAD database, including 171,906 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 0.36 (12146 hom., cov: 30)
  • Exomes 𝑓: 0.46 (159760 hom.)
• Consequence: PODXL ENST00000378555.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.61

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=1.0459315E-5).
• BP6: Variant 7-131511200-C-T is Benign according to our data. Variant chr7-131511200-C-T is described in ClinVar as [Benign]. Clinvar id is 1222221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PODXL	NM_001018111.3	c.334G>A	p.Gly112Ser	missense_variant	2/9	ENST00000378555.8	NP_001018121.1
PODXL	NM_005397.4	c.334G>A	p.Gly112Ser	missense_variant	2/8		NP_005388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PODXL	ENST00000378555.8	c.334G>A	p.Gly112Ser	missense_variant	2/9	1	NM_001018111.3	ENSP00000367817	P2
PODXL	ENST00000322985.9	c.334G>A	p.Gly112Ser	missense_variant	2/8	1		ENSP00000319782	A2
PODXL	ENST00000465001.1	n.525G>A		non_coding_transcript_exon_variant	3/3	4
PODXL	ENST00000446198.5	c.334G>A	p.Gly112Ser	missense_variant, NMD_transcript_variant	2/7	2		ENSP00000390152

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55002 AN: 151590 Hom.: 12130 Cov.: 30

Gnomad AFR AF: 0.0955

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.367

GnomAD3 exomes AF: 0.436 AC: 109490 AN: 251408 Hom.: 25577 AF XY: 0.436 AC XY: 59241 AN XY: 135864

Gnomad AFR exome AF: 0.0877

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.625

Gnomad SAS exome AF: 0.358

Gnomad FIN exome AF: 0.506

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.436

GnomAD4 exome AF: 0.461 AC: 673388 AN: 1461688 Hom.: 159760 Cov.: 58 AF XY: 0.459 AC XY: 333444 AN XY: 727152

Gnomad4 AFR exome AF: 0.0796

Gnomad4 AMR exome AF: 0.425

Gnomad4 ASJ exome AF: 0.396

Gnomad4 EAS exome AF: 0.591

Gnomad4 SAS exome AF: 0.356

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.478

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.363 AC: 55032 AN: 151708 Hom.: 12146 Cov.: 30 AF XY: 0.365 AC XY: 27093 AN XY: 74126

Gnomad4 AFR AF: 0.0953

Gnomad4 AMR AF: 0.380

Gnomad4 ASJ AF: 0.388

Gnomad4 EAS AF: 0.622

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.498

Gnomad4 NFE AF: 0.478

Gnomad4 OTH AF: 0.375

Alfa AF: 0.447 Hom.: 39543

Bravo AF: 0.344

TwinsUK AF: 0.481 AC: 1783

ALSPAC AF: 0.470 AC: 1812

ESP6500AA AF: 0.107 AC: 470

ESP6500EA AF: 0.473 AC: 4070

ExAC AF: 0.427 AC: 51851

Asia WGS AF: 0.505 AC: 1753 AN: 3476

EpiCase AF: 0.457

EpiControl AF: 0.445

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.012
DANN	Benign	0.48
DEOGEN2	Benign	0.057	T;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	0.000010	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.2	N;N
REVEL	Benign	0.042
Sift	Benign	0.38	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.017	B;B
Vest4		0.053
MPC		0.24
ClinPred		0.0048	T
GERP RS		-5.6
Varity_R		0.065
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: rs3735035; hg19: chr7-131195959; COSMIC: COSV59870570; COSMIC: COSV59870570;