12-108826127-C-G

Variant names:

• chr12-108826127-C-G
• rs6539455
• NM_018984.4:c.111-2766G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018984.4(SSH1):​c.111-2766G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 454,330 control chromosomes in the GnomAD database, including 9,385 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (4271 hom., cov: 31)
  • Exomes 𝑓: 0.14 (5114 hom.)
• Consequence: SSH1 NM_018984.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.193
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSH1	NM_018984.4	c.111-2766G>C		intron_variant	Intron 2 of 14	ENST00000326495.10	NP_061857.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSH1	ENST00000326495.10	c.111-2766G>C		intron_variant	Intron 2 of 14	1	NM_018984.4	ENSP00000315713.5

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30523 AN: 151828 Hom.: 4262 Cov.: 31

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.0677

Gnomad FIN AF: 0.0646

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.215

GnomAD2 exomes AF: 0.194 AC: 24570 AN: 126760 AF XY: 0.173

Gnomad AFR exome AF: 0.360

Gnomad AMR exome AF: 0.406

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.351

Gnomad FIN exome AF: 0.0543

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.144 AC: 43531 AN: 302386 Hom.: 5114 Cov.: 0 AF XY: 0.132 AC XY: 22752 AN XY: 172388

African (AFR) AF: 0.351 AC: 2966 AN: 8452

American (AMR) AF: 0.406 AC: 10859 AN: 26740

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 2103 AN: 10732

East Asian (EAS) AF: 0.346 AC: 3166 AN: 9158

South Asian (SAS) AF: 0.0690 AC: 4112 AN: 59578

European-Finnish (FIN) AF: 0.0632 AC: 781 AN: 12354

Middle Eastern (MID) AF: 0.180 AC: 497 AN: 2760

European-Non Finnish (NFE) AF: 0.107 AC: 16893 AN: 158458

Other (OTH) AF: 0.152 AC: 2154 AN: 14154

GnomAD4 genome AF: 0.201 AC: 30562 AN: 151944 Hom.: 4271 Cov.: 31 AF XY: 0.200 AC XY: 14839 AN XY: 74270

African (AFR) AF: 0.346 AC: 14336 AN: 41400

American (AMR) AF: 0.322 AC: 4918 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 679 AN: 3470

East Asian (EAS) AF: 0.329 AC: 1701 AN: 5166

South Asian (SAS) AF: 0.0680 AC: 327 AN: 4810

European-Finnish (FIN) AF: 0.0646 AC: 683 AN: 10568

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7248 AN: 67952

Other (OTH) AF: 0.213 AC: 449 AN: 2108

Alfa AF: 0.0888 Hom.: 183

Bravo AF: 0.236

Asia WGS AF: 0.165 AC: 572 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.2
DANN	Benign	0.62
PhyloP100		-0.19
PromoterAI		-0.057	Neutral
Mutation Taster		=100/0	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: rs6539455; hg19: chr12-109219903;