11-67307072-G-C

Variant names:

• chr11-67307072-G-C
• rs1861267103
• NM_017857.4:c.495G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017857.4(SSH3):​c.495G>C​(p.Leu165Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SSH3 NM_017857.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0890

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSH3	NM_017857.4	c.495G>C	p.Leu165Phe	missense_variant	Exon 5 of 14	ENST00000308127.9	NP_060327.3
SSH3	XM_047427177.1	c.495G>C	p.Leu165Phe	missense_variant	Exon 5 of 13		XP_047283133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSH3	ENST00000308127.9	c.495G>C	p.Leu165Phe	missense_variant	Exon 5 of 14	1	NM_017857.4	ENSP00000312081.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.495G>C (p.L165F) alteration is located in exon 5 (coding exon 5) of the SSH3 gene. This alteration results from a G to C substitution at nucleotide position 495, causing the leucine (L) at amino acid position 165 to be replaced by a phenylalanine (F). 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	Benign	0.28
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.1	M;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.8	D;.;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.021	D;.;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.94	P;D;.
Vest4		0.72
MutPred		0.29		Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);
MVP		0.57
MPC		0.66
ClinPred		0.93	D
GERP RS		1.6
Varity_R		0.22
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1861267103; hg19: chr11-67074543;