7-93131318-A-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.4654T>A(p.Tyr1552Asn) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMD9L NM_152703.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.11

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 7-93131318-A-T is Pathogenic according to our data. Variant chr7-93131318-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1320284.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14197153).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAMD9L	NM_152703.5	c.4654T>A	p.Tyr1552Asn	missense_variant	5/5	ENST00000318238.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMD9L	ENST00000318238.9	c.4654T>A	p.Tyr1552Asn	missense_variant	5/5	1	NM_152703.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Monosomy 7 myelodysplasia and leukemia syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Nov 04, 2021

The SAMD9L c.4654T>A (p.Tyr1552Asn) missense change is absent in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). This variant has been identified in an individual with a personal and family history of monosomy 7 where the variant was found to segregate with disease (PS4_supporting, PP1; internal data). Seven of seven in silico tools predict a benign effect of this variant on protein function, however these predictions have not been found to correlate with syndromic risk and are thus not considered supporting evidence of a pathogenic or benign effect (PMID: 34621053). This variant is located within the OB fold domain (PMID: 28545555) where pathogenic variants have been reported (PMID: 33328584, 34621053). To our knowledge, functional studies have not been performed for this variant, however other variants in the OB fold domain have been functionally characterized as pathogenic (PMID: 29217778; Ortolano Blood 2018, 132: Supp 1 3863, 34621053). In addition, the adjacent p.Val1551Leu missense change has been reported as de novo in an individual with pancytopenia and monosomy 7 (Ortolano Blood 2018, 132: Supp 1 3863). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria and expert opinion: PM2_supporting, PS4_supporting, PP1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.019	T;T;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.21	N
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D;D;D;.
REVEL	Benign	0.072
Sift	Benign	0.039	D;D;D;.
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		0.11	B;B;B;.
Vest4		0.51
MutPred		0.42		Gain of disorder (P = 0.021);Gain of disorder (P = 0.021);Gain of disorder (P = 0.021);.;
MVP		0.32
MPC		0.34
ClinPred		0.39	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-92760631;