7-93133008-AA-GG

Variant names:

• chr7-93133008-AA-GG
• NM_152703.5:c.2963_2964delTTinsCC
• SAMD9L p.Ile988Thr

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_152703.5(SAMD9L):​c.2963_2964delTTinsCC​(p.Ile988Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I988V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMD9L NM_152703.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.19
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_152703.5

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.2963_2964delTTinsCC	p.Ile988Thr	missense	N/A	NP_689916.2
	SAMD9L	NM_001303496.3		c.2963_2964delTTinsCC	p.Ile988Thr	missense	N/A	NP_001290425.1	Q8IVG5-1
	SAMD9L	NM_001303497.3		c.2963_2964delTTinsCC	p.Ile988Thr	missense	N/A	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.2963_2964delTTinsCC	p.Ile988Thr	missense	N/A	ENSP00000326247.4	Q8IVG5-1
	SAMD9L	ENST00000414791.6	TSL:1	c.2963_2964delTTinsCC	p.Ile988Thr	missense	N/A	ENSP00000396137.2	Q8IVG5-1
	SAMD9L	ENST00000437805.5	TSL:1	c.2963_2964delTTinsCC	p.Ile988Thr	missense	N/A	ENSP00000408796.1	Q8IVG5-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-92762321;