rs1554341158

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr7-93133016-G-A
• chr7-93133016-G-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_152703.5(SAMD9L):​c.2956C>T​(p.Arg986Cys) 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001778793: Published in vitro functional studies demonstrate a damaging effect, as this variant results in a significant decrease in cell proliferation (Tesi et al., 2017)" and additional evidence is available in ClinVar. 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: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 3.10
• Publications: 5 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, Orphanet, PanelApp Australia, G2P
• SAMD9L-related spectrum and myeloid neoplasm risk

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• spinocerebellar ataxia 49

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001778793: Published in vitro functional studies demonstrate a damaging effect, as this variant results in a significant decrease in cell proliferation (Tesi et al., 2017);; SCV002235382: Experimental studies have shown that this missense change affects SAMD9L function (PMID: 28202457, 30046003).
• 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, 0.943
• PP5: Variant 7-93133016-G-A is Pathogenic according to our data. Variant chr7-93133016-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 446530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152703.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMD9L	NM_152703.5	MANE Select	c.2956C>T	p.Arg986Cys	missense	Exon 5 of 5	NP_689916.2
	SAMD9L	NM_001303496.3		c.2956C>T	p.Arg986Cys	missense	Exon 5 of 5	NP_001290425.1	Q8IVG5-1
	SAMD9L	NM_001303497.3		c.2956C>T	p.Arg986Cys	missense	Exon 6 of 6	NP_001290426.1	Q8IVG5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMD9L	ENST00000318238.9	TSL:1 MANE Select	c.2956C>T	p.Arg986Cys	missense	Exon 5 of 5	ENSP00000326247.4	Q8IVG5-1
	SAMD9L	ENST00000414791.6	TSL:1	c.2956C>T	p.Arg986Cys	missense	Exon 2 of 2	ENSP00000396137.2	Q8IVG5-1
	SAMD9L	ENST00000437805.5	TSL:1	c.2956C>T	p.Arg986Cys	missense	Exon 6 of 6	ENSP00000408796.1	Q8IVG5-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Ataxia-pancytopenia syndrome (4)
3	-	-	not provided (3)
2	-	-	Monosomy 7 myelodysplasia and leukemia syndrome 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.38	B
Vest4		0.74
MutPred		0.88		Gain of sheet (P = 0.0827)
MVP		0.42
MPC		0.75
ClinPred		0.91	D
GERP RS		-0.066
Varity_R		0.38
gMVP		0.69
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554341158; hg19: chr7-92762329; COSMIC: COSV59083574; COSMIC: COSV59083574;