21-14516961-C-T

Variant names:

• chr21-14516961-C-T
• rs1987947108
• ENST00000619120.4:c.3G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001286523.2(SAMSN1):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SAMSN1 NM_001286523.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.88

Genes affected

SAMSN1 (HGNC:10528): (SAM domain, SH3 domain and nuclear localization signals 1) SAMSN1 is a member of a novel gene family of putative adaptors and scaffold proteins containing SH3 and SAM (sterile alpha motif) domains (Claudio et al., 2001 [PubMed 11536050]).[supplied by OMIM, Mar 2008]

LOC124905053 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 8 codons. Genomic position: 14516942. Lost 0.024 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMSN1	NM_022136.5	c.210G>A	p.Met70Ile	missense_variant	Exon 3 of 8	ENST00000400566.6	NP_071419.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAMSN1	ENST00000400566.6	c.210G>A	p.Met70Ile	missense_variant	Exon 3 of 8	1	NM_022136.5	ENSP00000383411.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461076 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726836

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.210G>A (p.M70I) alteration is located in exon 3 (coding exon 3) of the SAMSN1 gene. This alteration results from a G to A substitution at nucleotide position 210, causing the methionine (M) at amino acid position 70 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T;.;T;.
Eigen	Benign	-0.011
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;D;D;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.7	N;.;.;N
REVEL	Benign	0.088
Sift	Benign	0.69	T;.;.;T
Sift4G	Benign	0.54	T;.;T;T
Polyphen		0.010	B;.;.;.
Vest4		0.32
MutPred		0.32		Gain of methylation at K69 (P = 0.0223);.;.;.;
MVP		0.53
MPC		0.16
ClinPred		0.72	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.30

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: rs1987947108; hg19: chr21-15889282;