chr11-67303632-C-A

Variant names:

• chr11-67303632-C-A
• NM_017857.4:c.7C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017857.4(SSH3):​c.7C>A​(p.Leu3Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000733 in 1,364,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SSH3 NM_017857.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

Genes affected

SSH3 (HGNC:30581): (slingshot protein phosphatase 3) The ADF (actin-depolymerizing factor)/cofilin family (see MIM 601442) is composed of stimulus-responsive mediators of actin dynamics. ADF/cofilin proteins are inactivated by kinases such as LIM domain kinase-1 (LIMK1; MIM 601329). The SSH family appears to play a role in actin dynamics by reactivating ADF/cofilin proteins in vivo (Niwa et al., 2002 [PubMed 11832213]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31026056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSH3	NM_017857.4	c.7C>A	p.Leu3Met	missense_variant	Exon 1 of 14	ENST00000308127.9	NP_060327.3
SSH3	XM_047427177.1	c.7C>A	p.Leu3Met	missense_variant	Exon 1 of 13		XP_047283133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSH3	ENST00000308127.9	c.7C>A	p.Leu3Met	missense_variant	Exon 1 of 14	1	NM_017857.4	ENSP00000312081.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.33e-7 AC: 1 AN: 1364720 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 673672

Gnomad4 AFR exome AF: 0.0000353

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7C>A (p.L3M) alteration is located in exon 1 (coding exon 1) of the SSH3 gene. This alteration results from a C to A substitution at nucleotide position 7, causing the leucine (L) at amino acid position 3 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.79	P;.
Vest4		0.41
MutPred		0.38		Gain of MoRF binding (P = 0.059);Gain of MoRF binding (P = 0.059);
MVP		0.60
MPC		0.69
ClinPred		0.84	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.49
gMVP		0.38

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-67071103;