Genetic Variant SYNPO:p.Asp67His (chr5-150618566-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000394243.5(SYNPO):c.199G>C(p.Asp67His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000987 in 1,550,418 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. D67N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 1 hom. )

Consequence

SYNPO
ENST00000394243.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.11

Publications

8 publications found

Variant links:

Genes affected

SYNPO (HGNC:30672): (synaptopodin) Synaptopodin is an actin-associated protein that may play a role in actin-based cell shape and motility. The name synaptopodin derives from the protein's associations with postsynaptic densities and dendritic spines and with renal podocytes (Mundel et al., 1997 [PubMed 9314539]).[supplied by OMIM, Mar 2008]

SYNPO links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048027635).

BS2

High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
SYNPO	NM_001166208.2 link	c.199G>C	p.Asp67His	missense_variant	Exon 2 of 3	NP_001159680.1	Q8N3V7-1
SYNPO	NM_001166209.2 link	c.199G>C	p.Asp67His	missense_variant	Exon 2 of 3	NP_001159681.1	Q8N3V7-1
SYNPO	XM_006714755.4 link	c.199G>C	p.Asp67His	missense_variant	Exon 2 of 4	XP_006714818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNPO	ENST00000394243.5 link	c.199G>C	p.Asp67His	missense_variant	Exon 2 of 3	1		ENSP00000377789.1		Q8N3V7-1
SYNPO	ENST00000522122.1 link	c.199G>C	p.Asp67His	missense_variant	Exon 2 of 3	2		ENSP00000428378.1		Q8N3V7-1

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000130

AC:

AN:

153396

AF XY:

0.0000614

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.0000406

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000579

AC:

AN:

1398212

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

689424

show subpopulations

African (AFR)

AF:

0.00222

AC:

AN:

31572

American (AMR)

AF:

0.000140

AC:

AN:

35682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25150

East Asian (EAS)

AF:

0.00

AC:

AN:

35702

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078204

Other (OTH)

AF:

0.0000863

AC:

AN:

57922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000473

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00169

AC:

AN:

41504

American (AMR)

AF:

0.000131

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000260

Hom.:

ExAC

AF:

0.000190

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.070

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.27

.;T

M_CAP

Benign

0.0023

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PhyloP100

1.1

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.080

N;N

REVEL

Benign

0.040

Sift

Uncertain

0.016

D;D

Sift4G

Benign

0.13

T;T

Polyphen

0.016

B;B

Vest4

0.029

MVP

0.10

MPC

0.41

ClinPred

0.035

GERP RS

3.6

Varity_R

0.062

gMVP

0.079

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over