Genetic Variant SAMSN1:p.Glu225Asp (chr21-14500622-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_022136.5(SAMSN1):c.675G>C(p.Glu225Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SAMSN1
NM_022136.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.156

Variant links:

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]

SAMSN1 links:

LOC124905053 (HGNC:):

LOC124905053 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29136825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMSN1	NM_022136.5 link	c.675G>C	p.Glu225Asp	missense_variant	Exon 6 of 8	ENST00000400566.6	NP_071419.3	Q9NSI8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAMSN1	ENST00000400566.6 link	c.675G>C	p.Glu225Asp	missense_variant	Exon 6 of 8	1	NM_022136.5	ENSP00000383411.2		Q9NSI8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249536

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135392

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727220

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000153

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.675G>C (p.E225D) alteration is located in exon 6 (coding exon 6) of the SAMSN1 gene. This alteration results from a G to C substitution at nucleotide position 675, causing the glutamic acid (E) at amino acid position 225 to be replaced by an aspartic acid (D). 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

Benign

0.13

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;T;.;T;.

Eigen

Benign

-0.097

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.85

T;T;T;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.29

T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Pathogenic

3.0

.;M;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.1

N;N;.;.;N

REVEL

Benign

0.16

Sift

Benign

0.031

D;D;.;.;D

Sift4G

Uncertain

0.036

D;T;.;T;T

Polyphen

1.0

D;D;.;.;.

Vest4

0.47

MutPred

0.23

.;Gain of catalytic residue at E225 (P = 0.1477);.;.;.;

MVP

0.56

MPC

0.53

ClinPred

0.92

GERP RS

-3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over