chr12-108788427-C-G

Variant names:

• chr12-108788427-C-G
• rs1029514308
• NM_018984.4:c.2711G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018984.4(SSH1):​c.2711G>C​(p.Arg904Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R904H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SSH1 NM_018984.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.53
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2711G>C	p.Arg904Pro	missense	Exon 15 of 15	NP_061857.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SSH1	ENST00000326495.10	TSL:1 MANE Select	c.2711G>C	p.Arg904Pro	missense	Exon 15 of 15	ENSP00000315713.5	Q8WYL5-1
	SSH1	ENST00000877978.1		c.2642G>C	p.Arg881Pro	missense	Exon 14 of 14	ENSP00000548037.1
	SSH1	ENST00000546433.5	TSL:5	n.*1704G>C		non_coding_transcript_exon	Exon 7 of 7	ENSP00000447629.1	H0YHR3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437022 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 712982

African (AFR) AF: 0.00 AC: 0 AN: 32462

American (AMR) AF: 0.00 AC: 0 AN: 40750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24352

East Asian (EAS) AF: 0.00 AC: 0 AN: 39516

South Asian (SAS) AF: 0.00 AC: 0 AN: 82018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101612

Other (OTH) AF: 0.00 AC: 0 AN: 59204

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.33		Gain of catalytic residue at P899 (P = 0.0017)
MVP		0.37
MPC		0.36
ClinPred		0.86	D
GERP RS		5.6
Varity_R		0.31
gMVP		0.54
Mutation Taster		=80/20	polymorphism

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: rs1029514308; hg19: chr12-109182203;