Genetic Variant SMS:p.Met1? (chrX-21940827-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_004595.5(SMS):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

SMS
NM_004595.5 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.176

Publications

0 publications found

Variant links:

Genes affected

SMS (HGNC:11123): (spermine synthase) This gene encodes a protein belonging to the spermidine/spermin synthase family and catalyzes the production of spermine from spermidine. Pseudogenes of this gene are located on chromosomes 1, 5, 6 and X. Mutations in this gene cause an X-linked intellectual disability called Snyder-Robinson Syndrome (SRS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

SMS Gene-Disease associations (from GenCC):

syndromic X-linked intellectual disability Snyder type
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P, ClinGen

SMS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 12 codons. Genomic position: 21940858. Lost 0.031 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004595.5. 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
	SMS	NM_004595.5	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 11	NP_004586.2
	SMS	NM_001258423.2		c.3G>A	p.Met1?	start_lost	Exon 1 of 9	NP_001245352.1	P52788-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMS	ENST00000404933.7	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 11	ENSP00000385746.2	P52788-1
SMS	ENST00000853889.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 12	ENSP00000523948.1
SMS	ENST00000955899.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 12	ENSP00000625958.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1012079

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

325993

African (AFR)

AF:

0.00

AC:

AN:

21750

American (AMR)

AF:

0.00

AC:

AN:

25917

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17535

East Asian (EAS)

AF:

0.00

AC:

AN:

24230

South Asian (SAS)

AF:

0.00

AC:

AN:

48011

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

803851

Other (OTH)

AF:

0.00

AC:

AN:

42497

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.028

FATHMM_MKL

Benign

0.50

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-0.50

PhyloP100

0.18

PROVEAN

Benign

-0.60

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

Sift4G

Benign

0.18

Polyphen

0.0040

Vest4

0.56

MutPred

0.94

Loss of disorder (P = 0.0922)

MVP

0.99

ClinPred

0.99

GERP RS

2.8

PromoterAI

-0.27

Neutral

(source)

Varity_R

0.90

gMVP

0.46

Mutation Taster

=35/165

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over