rs1556885815

Positions:

• chrX-53381057-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP2 PP3_Strong

The NM_006306.4(SMC1A):​c.3468T>G​(p.Asp1156Glu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0034 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SMC1A NM_006306.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.38

Genes affected

SMC1A (HGNC:11111): (structural maintenance of chromosomes 1A) Proper cohesion of sister chromatids is a prerequisite for the correct segregation of chromosomes during cell division. The cohesin multiprotein complex is required for sister chromatid cohesion. This complex is composed partly of two structural maintenance of chromosomes (SMC) proteins, SMC3 and either SMC1B or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with BRCA1 and is phosphorylated by ATM, indicating a potential role for this protein in DNA repair. This gene, which belongs to the SMC gene family, is located in an area of the X-chromosome that escapes X inactivation. Mutations in this gene result in Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SMC1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC1A	NM_006306.4	c.3468T>G	p.Asp1156Glu	missense_variant	23/25	ENST00000322213.9
SMC1A	NM_001281463.1	c.3402T>G	p.Asp1134Glu	missense_variant	24/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC1A	ENST00000322213.9	c.3468T>G	p.Asp1156Glu	missense_variant	23/25	1	NM_006306.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 4 AN: 108590 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 31344 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000354

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000383

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00340 AC: 3575 AN: 1052218 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 341022

Gnomad4 AFR exome AF: 0.00259

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.000590

Gnomad4 SAS exome AF: 0.00127

Gnomad4 FIN exome AF: 0.000102

Gnomad4 NFE exome AF: 0.00405

Gnomad4 OTH exome AF: 0.00303

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000368 AC: 4 AN: 108649 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 31405

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000354

Gnomad4 NFE AF: 0.0000384

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

Developmental and epileptic encephalopathy, 85, with or without midline brain defects Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.3468T>Gp.Asp1156Glu in SMC1A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asp1156Glu variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain_significance with a status of criteria provided, single submitter. The amino acid change p.Asp1156Glu in SMC1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 1156 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance VUS. -

Congenital muscular hypertrophy-cerebral syndrome;C5393312:Developmental and epileptic encephalopathy, 85, with or without midline brain defects Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.021	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.87		Loss of catalytic residue at D1159 (P = 0.2854);.;
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		1.0

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

Other links and lift over

dbSNP: rs1556885815; hg19: chrX-53407978;