7-93133300-A-G

Variant names:

• chr7-93133300-A-G
• rs1554341277
• NM_152703.5:c.2672T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_152703.5(SAMD9L):​c.2672T>C​(p.Ile891Thr) variant causes a missense change involving the alteration of a 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I891F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMD9L NM_152703.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.58
• Publications: 1 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 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_152703.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• PP5: Variant 7-93133300-A-G is Pathogenic according to our data. Variant chr7-93133300-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 446529.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMD9L	NM_152703.5	MANE Select	c.2672T>C	p.Ile891Thr	missense	Exon 5 of 5	NP_689916.2
	SAMD9L	NM_001303496.3		c.2672T>C	p.Ile891Thr	missense	Exon 5 of 5	NP_001290425.1
	SAMD9L	NM_001303497.3		c.2672T>C	p.Ile891Thr	missense	Exon 6 of 6	NP_001290426.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMD9L	ENST00000318238.9	TSL:1 MANE Select	c.2672T>C	p.Ile891Thr	missense	Exon 5 of 5	ENSP00000326247.4
	SAMD9L	ENST00000414791.6	TSL:1	c.2672T>C	p.Ile891Thr	missense	Exon 2 of 2	ENSP00000396137.2
	SAMD9L	ENST00000437805.5	TSL:1	c.2672T>C	p.Ile891Thr	missense	Exon 6 of 6	ENSP00000408796.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Ataxia-pancytopenia syndrome Pathogenic:1 Other:1

Dec 10, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		8.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.74		Loss of stability (P = 0.002)
MVP		0.55
MPC		0.81
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.59
gMVP		0.58
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs1554341277; hg19: chr7-92762613;