8-118439896-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_207506.3(SAMD12):c.258G>C(p.Leu86Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMD12 NM_207506.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

Genes affected

SAMD12 (HGNC:31750): (sterile alpha motif domain containing 12) Predicted to be involved in transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to be active in cytoplasmic side of plasma membrane. Implicated in familial adult myoclonic epilepsy 1. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAMD12	NM_207506.3	c.258G>C	p.Leu86Phe	missense_variant	3/4	ENST00000314727.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMD12	ENST00000314727.9	c.258G>C	p.Leu86Phe	missense_variant	3/4	1	NM_207506.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251302 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

SAMD12: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D;.;D
REVEL	Pathogenic	0.90
Sift	Benign	0.082	T;.;T
Sift4G	Benign	0.11	T;.;T
Polyphen		1.0	D;.;D
Vest4		0.91
MutPred		0.86		Gain of methylation at K87 (P = 0.0293);Gain of methylation at K87 (P = 0.0293);Gain of methylation at K87 (P = 0.0293);
MVP		0.95
MPC		0.44
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.42
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs1335979436; hg19: chr8-119452135;