chr7-131508980-C-T

Variant names:

• chr7-131508980-C-T
• rs3212298
• NM_001018111.3:c.1072G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:4
• Conservation: PhyloP100: -2.88
• Publications: 12 publications found

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]

PODXL Gene-Disease associations (from GenCC):

• atypical juvenile parkinsonism

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• young-onset Parkinson disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1236309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018111.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PODXL	NM_001018111.3	MANE Select	c.1072G>A	p.Val358Ile	missense	Exon 5 of 9	NP_001018121.1
	PODXL	NM_005397.4		c.976G>A	p.Val326Ile	missense	Exon 4 of 8	NP_005388.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PODXL	ENST00000378555.8	TSL:1 MANE Select	c.1072G>A	p.Val358Ile	missense	Exon 5 of 9	ENSP00000367817.3
	PODXL	ENST00000322985.9	TSL:1	c.976G>A	p.Val326Ile	missense	Exon 4 of 8	ENSP00000319782.9
	PODXL	ENST00000923671.1		c.1072G>A	p.Val358Ile	missense	Exon 5 of 9	ENSP00000593730.1

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

GnomAD2 exomes AF: 0.0628 AC: 15795 AN: 251452 AF XY: 0.0654

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 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

African (AFR) AF: 0.0146 AC: 488 AN: 33474

American (AMR) AF: 0.0250 AC: 1116 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0556 AC: 1453 AN: 26130

East Asian (EAS) AF: 0.220 AC: 8715 AN: 39688

South Asian (SAS) AF: 0.103 AC: 8840 AN: 86234

European-Finnish (FIN) AF: 0.0443 AC: 2365 AN: 53404

Middle Eastern (MID) AF: 0.0610 AC: 352 AN: 5766

European-Non Finnish (NFE) AF: 0.0445 AC: 49402 AN: 1111390

Other (OTH) AF: 0.0582 AC: 3513 AN: 60370

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

African (AFR) AF: 0.0168 AC: 697 AN: 41534

American (AMR) AF: 0.0251 AC: 384 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0542 AC: 188 AN: 3470

East Asian (EAS) AF: 0.234 AC: 1212 AN: 5170

South Asian (SAS) AF: 0.105 AC: 509 AN: 4826

European-Finnish (FIN) AF: 0.0463 AC: 491 AN: 10604

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0455 AC: 3092 AN: 68014

Other (OTH) AF: 0.0482 AC: 102 AN: 2114

Alfa AF: 0.0488 Hom.: 1115

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	PODXL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.84	N
PhyloP100		-2.9
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.010
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.013
MPC		0.19
ClinPred		0.0012	T
GERP RS		-7.7
Varity_R		0.017
gMVP		0.11
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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