Genetic Variant SSH1:p.Glu867Lys (chr12-108788539-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018984.4(SSH1):c.2599G>A(p.Glu867Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000802 in 1,571,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

SSH1
NM_018984.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.184

Publications

0 publications found

Variant links:

Genes affected

SSH1 (HGNC:30579): (slingshot protein phosphatase 1) The protein encoded by this gene belongs to the slingshot homolog (SSH) family of phosphatases, which regulate actin filament dynamics. The SSH proteins dephosphorylate and activate the actin binding/depolymerizing factor cofilin, which subsequently binds to actin filaments and stimulates their disassembly. Cofilin is inactivated by kinases such as LIM domain kinase-1 (LIMK1), which may also be dephosphorylated and inactivated by SSH proteins. The SSH family thus appears to play a role in actin dynamics by reactivating cofilin proteins. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

SSH1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009952933).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018984.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SSH1	NM_018984.4	MANE Select	c.2599G>A	p.Glu867Lys	missense	Exon 15 of 15	NP_061857.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SSH1	ENST00000326495.10	TSL:1 MANE Select	c.2599G>A	p.Glu867Lys	missense	Exon 15 of 15	ENSP00000315713.5	Q8WYL5-1
SSH1	ENST00000877978.1		c.2530G>A	p.Glu844Lys	missense	Exon 14 of 14	ENSP00000548037.1
SSH1	ENST00000546433.5	TSL:5	n.*1592G>A		non_coding_transcript_exon	Exon 7 of 7	ENSP00000447629.1	H0YHR3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000138

AC:

AN:

217156

AF XY:

0.000205

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000167

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:

0.0000845

AC:

120

AN:

1419310

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

701288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32090

American (AMR)

AF:

0.000126

AC:

AN:

39608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23294

East Asian (EAS)

AF:

0.00

AC:

AN:

39294

South Asian (SAS)

AF:

0.00129

AC:

102

AN:

79096

European-Finnish (FIN)

AF:

0.0000389

AC:

AN:

51352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5550

European-Non Finnish (NFE)

AF:

0.00000642

AC:

AN:

1090662

Other (OTH)

AF:

0.0000685

AC:

AN:

58364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00124

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000173

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.9

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.043

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.63

M_CAP

Benign

0.0024

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-0.18

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.85

REVEL

Benign

0.17

Sift

Benign

0.12

Sift4G

Benign

0.85

Polyphen

0.0050

Vest4

0.037

MutPred

0.24

Gain of catalytic residue at L871 (P = 0.0022)

MVP

0.17

MPC

0.28

ClinPred

0.031

GERP RS

1.9

Varity_R

0.075

gMVP

0.16

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over