dbSNP rs1554341277: SAMD9L:p.Ile891Thr (chr7-93133300-A-G) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

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

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 8.58

Publications

1 publications found

Variant links:

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

SAMD9L links:

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ACMG classification

Classification was made for transcript

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

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	Q8IVG5-1
SAMD9L	NM_001303497.3		c.2672T>C	p.Ile891Thr	missense	Exon 6 of 6	NP_001290426.1	Q8IVG5-1

Ensembl Transcripts

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	Q8IVG5-1
SAMD9L	ENST00000414791.6	TSL:1	c.2672T>C	p.Ile891Thr	missense	Exon 2 of 2	ENSP00000396137.2	Q8IVG5-1
SAMD9L	ENST00000437805.5	TSL:1	c.2672T>C	p.Ile891Thr	missense	Exon 6 of 6	ENSP00000408796.1	Q8IVG5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ataxia-pancytopenia syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.86

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.78

MutationAssessor

Pathogenic

2.9

PhyloP100

8.6

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.59

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.79

MutPred

0.74

Loss of stability (P = 0.002)

MVP

0.55

MPC

0.81

ClinPred

0.99

GERP RS

5.2

Varity_R

0.59

gMVP

0.58

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over