7-131506614-C-G

Variant names:

• chr7-131506614-C-G
• rs869312171
• NM_001018111.3:c.1214G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001018111.3(PODXL):​c.1214G>C​(p.Ser405Thr) variant causes a missense 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S405N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PODXL NM_001018111.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.05
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0609186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PODXL	NM_001018111.3	c.1214G>C	p.Ser405Thr	missense_variant	Exon 6 of 9	ENST00000378555.8	NP_001018121.1
PODXL	NM_005397.4	c.1118G>C	p.Ser373Thr	missense_variant	Exon 5 of 8		NP_005388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PODXL	ENST00000378555.8	c.1214G>C	p.Ser405Thr	missense_variant	Exon 6 of 9	1	NM_001018111.3	ENSP00000367817.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.035
DANN	Benign	0.63
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.22	T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		-2.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.013
Sift	Benign	0.049	D;T
Sift4G	Benign	0.39	T;T
Polyphen		0.14	B;B
Vest4		0.062
MutPred		0.43		Gain of phosphorylation at S405 (P = 0.1778);.;
MVP		0.099
MPC		0.47
ClinPred		0.14	T
GERP RS		-3.8
Varity_R		0.098
gMVP		0.27
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs869312171; hg19: chr7-131191373;