7-93131351-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_152703.5(SAMD9L):c.4621G>C(p.Glu1541Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SAMD9L NM_152703.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.669

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.075212985).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000547 (8/1461294) while in subpopulation AMR AF= 0.000157 (7/44572). AF 95% confidence interval is 0.000073. There are 0 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAMD9L	NM_152703.5	c.4621G>C	p.Glu1541Gln	missense_variant	5/5	ENST00000318238.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMD9L	ENST00000318238.9	c.4621G>C	p.Glu1541Gln	missense_variant	5/5	1	NM_152703.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461294 Hom.: 0 Cov.: 34 AF XY: 0.00000963 AC XY: 7 AN XY: 726942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 1476631). This variant has not been reported in the literature in individuals affected with SAMD9L-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1541 of the SAMD9L protein (p.Glu1541Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.18
Dann	Benign	0.84
DEOGEN2	Benign	0.012	T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.075	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N;N;N;.
REVEL	Benign	0.0080
Sift	Benign	0.20	T;T;T;.
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.078	B;B;B;.
Vest4		0.072
MutPred		0.23		Loss of ubiquitination at K1543 (P = 0.0736);Loss of ubiquitination at K1543 (P = 0.0736);Loss of ubiquitination at K1543 (P = 0.0736);.;
MVP		0.22
MPC		0.23
ClinPred		0.10	T
GERP RS		1.2
Varity_R		0.052
gMVP		0.34

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: chr7-92760664;