rs61732077

Variant names:

• chrX-21992677-A-C
• rs61732077
• NM_004595.5:c.1026A>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004595.5(SMS):​c.1026A>C​(p.Ser342Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00548 in 1,194,374 control chromosomes in the GnomAD database, including 12 homozygotes. There are 2,066 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., 97 hem., cov: 23)
  • Exomes 𝑓: 0.0057 (11 hom. 1969 hem.)
• Consequence: SMS NM_004595.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.398
• Publications: 0 publications found

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), Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant X-21992677-A-C is Benign according to our data. Variant chrX-21992677-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.398 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 97 XL gene

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.1026A>C	p.Ser342Ser	synonymous	Exon 10 of 11	NP_004586.2
	SMS	NM_001258423.2		c.867A>C	p.Ser289Ser	synonymous	Exon 8 of 9	NP_001245352.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMS	ENST00000404933.7	TSL:1 MANE Select	c.1026A>C	p.Ser342Ser	synonymous	Exon 10 of 11	ENSP00000385746.2
	SMS	ENST00000853889.1		c.1044A>C	p.Ser348Ser	synonymous	Exon 11 of 12	ENSP00000523948.1
	SMS	ENST00000955899.1		c.1044A>C	p.Ser348Ser	synonymous	Exon 11 of 12	ENSP00000625958.1

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 425 AN: 112145 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

Gnomad ASJ AF: 0.00491

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000731

Gnomad FIN AF: 0.000329

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00672

Gnomad OTH AF: 0.00464

GnomAD2 exomes AF: 0.00359 AC: 657 AN: 183041 AF XY: 0.00370

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00281

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000562

Gnomad NFE exome AF: 0.00655

Gnomad OTH exome AF: 0.00487

GnomAD4 exome AF: 0.00565 AC: 6118 AN: 1082175 Hom.: 11 Cov.: 27 AF XY: 0.00565 AC XY: 1969 AN XY: 348695

African (AFR) AF: 0.000766 AC: 20 AN: 26104

American (AMR) AF: 0.00128 AC: 45 AN: 35172

Ashkenazi Jewish (ASJ) AF: 0.00311 AC: 60 AN: 19270

East Asian (EAS) AF: 0.00 AC: 0 AN: 30148

South Asian (SAS) AF: 0.00112 AC: 60 AN: 53726

European-Finnish (FIN) AF: 0.00136 AC: 55 AN: 40521

Middle Eastern (MID) AF: 0.000845 AC: 3 AN: 3549

European-Non Finnish (NFE) AF: 0.00686 AC: 5682 AN: 828173

Other (OTH) AF: 0.00424 AC: 193 AN: 45512

GnomAD4 genome AF: 0.00379 AC: 425 AN: 112199 Hom.: 1 Cov.: 23 AF XY: 0.00282 AC XY: 97 AN XY: 34367

African (AFR) AF: 0.000939 AC: 29 AN: 30882

American (AMR) AF: 0.00132 AC: 14 AN: 10578

Ashkenazi Jewish (ASJ) AF: 0.00491 AC: 13 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.000733 AC: 2 AN: 2727

European-Finnish (FIN) AF: 0.000329 AC: 2 AN: 6080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00672 AC: 358 AN: 53275

Other (OTH) AF: 0.00458 AC: 7 AN: 1527

Alfa AF: 0.00553 Hom.: 50

Bravo AF: 0.00380

EpiCase AF: 0.00689

EpiControl AF: 0.00634

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Syndromic X-linked intellectual disability Snyder type (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	SMS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.11
DANN	Benign	0.65
PhyloP100		-0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61732077; hg19: chrX-22010795;