7-93133016-G-T

Variant names:

• chr7-93133016-G-T
• rs1554341158
• NM_152703.5:c.2956C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_152703.5(SAMD9L):​c.2956C>A​(p.Arg986Ser) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R986H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMD9L NM_152703.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.10
• Publications: 0 publications found

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]

SAMD9L Gene-Disease associations (from GenCC):

• ataxia-pancytopenia syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• spinocerebellar ataxia 49

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-93133015-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1190635.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMD9L	NM_152703.5	c.2956C>A	p.Arg986Ser	missense_variant	Exon 5 of 5	ENST00000318238.9	NP_689916.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAMD9L	ENST00000318238.9	c.2956C>A	p.Arg986Ser	missense_variant	Exon 5 of 5	1	NM_152703.5	ENSP00000326247.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

May 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with serine at codon 986 of the SAMD9L protein (p.Arg986Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SAMD9L-related conditions. ClinVar contains an entry for this variant (Variation ID: 691978). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This variant disrupts the p.Arg986 amino acid residue in SAMD9L. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28202457, 29146883, 30046003). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Apr 02, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ataxia-pancytopenia syndrome Uncertain:1

Jul 19, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This SAMD9L variant is absent from large population datasets and has not been reported in the literature, to our knowledge. A different missense variant at the same position (p.Arg986Cys) has been previously reported in association with disease. Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the second predicts that it would be tolerated. However, these algorithms have low specificity, especially for predicting the functional impact of gain of function variants9. Additionally, bioinformatic analysis predicts that this variant would not affect normal exon 5 splicing, although this has not been confirmed experimentally to our knowledge. The clinical significance of c.2956C>A is uncertain at this time.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.0	.;.;T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M;M
PhyloP100		3.1
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.76
ClinPred		0.87	D
GERP RS		-0.066
Varity_R		0.55
gMVP		0.75
Mutation Taster		=29/71	disease causing

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: rs1554341158; hg19: chr7-92762329;