7-93133332-G-T

Position:

• chr7-93133332-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_152703.5(SAMD9L):​c.2640C>A​(p.His880Gln) 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 benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMD9L NM_152703.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:5 O:1
• Conservation: PhyloP100: 0.0810

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-93133332-G-T is Pathogenic according to our data. Variant chr7-93133332-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 242372.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-93133332-G-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.32390356). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SAMD9L	NM_152703.5	c.2640C>A	p.His880Gln	missense_variant	5/5	ENST00000318238.9	NP_689916.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SAMD9L	ENST00000318238.9	c.2640C>A	p.His880Gln	missense_variant	5/5	1	NM_152703.5	ENSP00000326247.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ataxia-pancytopenia syndrome Pathogenic:2 Other:1

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	Jun 06, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 10, 2020	- -

SAMD9L-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2024

The SAMD9L c.2640C>A variant is predicted to result in the amino acid substitution p.His880Gln. This variant has been reported in the heterozygous state in a family with ataxia-pancytopenia syndrome (ATXPC) (Chen et al. 2016. PubMed ID: 27259050). This variant has also been reported in individuals with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (Wong et al. 2018. PubMed ID: 30046003; Sahoo et al. 2021. PubMed ID: 34621053. Table S6; Allenspach et al. 2021. PubMed ID: 33724365). Functional studies showed that this variant affects the cell cycle progression (Wong et al. 2018. PubMed ID: 30046003; Allenspach et al. 2021. PubMed ID: 33724365). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Monosomy 7 myelodysplasia and leukemia syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 10, 2020

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 09, 2023

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 880 of the SAMD9L protein (p.His880Gln). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SAMD9L protein function. ClinVar contains an entry for this variant (Variation ID: 242372). This missense change has been observed in individual(s) with ataxia-pancytopenia syndrome (PMID: 27259050, 30046003). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;T
Eigen	Benign	-0.0036
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.71	.;.;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;M;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.084
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.033	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.60
MutPred		0.31		Gain of disorder (P = 0.0953);Gain of disorder (P = 0.0953);Gain of disorder (P = 0.0953);
MVP		0.36
MPC		0.66
ClinPred		0.98	D
GERP RS		0.10
Varity_R		0.31
gMVP		0.39

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: rs878855336; hg19: chr7-92762645;