7-93131343-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152703.5(SAMD9L):c.4629A>C(p.Lys1543Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K1543K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SAMD9L NM_152703.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.157

Genes affected

SAMD9L (HGNC:1349): (sterile alpha motif domain containing 9 like) This gene encodes a cytoplasmic protein that acts as a tumor suppressor but also plays a key role in cell proliferation and the innate immune response to viral infection. The encoded protein contains an N-terminal sterile alpha motif domain. Naturally occurring mutations in this gene are associated with myeloid disorders such as juvenile myelomonocytic leukemia, acute myeloid leukemia, and myelodysplastic syndrome. Naturally occurring mutations are also associated with hepatitis-B related hepatocellular carcinoma, normophosphatemic familial tumoral calcinosis, and ataxia-pancytopenia syndrome. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19108099).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAMD9L	NM_152703.5	c.4629A>C	p.Lys1543Asn	missense_variant	5/5	ENST00000318238.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMD9L	ENST00000318238.9	c.4629A>C	p.Lys1543Asn	missense_variant	5/5	1	NM_152703.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250580 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135428

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461366 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 726984

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000225 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

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

GeneDx

Jan 31, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28545555) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	15
Dann	Benign	0.92
DEOGEN2	Benign	0.0059	T;T;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.38	N
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.59	N;N;N;.
REVEL	Benign	0.088
Sift	Benign	0.29	T;T;T;.
Sift4G	Benign	0.23	T;T;T;D
Polyphen		0.99	D;D;D;.
Vest4		0.23
MutPred		0.65		Loss of methylation at K1543 (P = 0.0021);Loss of methylation at K1543 (P = 0.0021);Loss of methylation at K1543 (P = 0.0021);.;
MVP		0.39
MPC		0.31
ClinPred		0.12	T
GERP RS		1.2
Varity_R		0.048
gMVP		0.56

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: rs201068807; hg19: chr7-92760656;