rs1556889577

Positions:

• chrX-53405528-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_006306.4(SMC1A):​c.1876C>T​(p.Arg626Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,156 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: SMC1A NM_006306.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.35

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMC1A. . Gene score misZ 6.4479 (greater than the threshold 3.09). GenCC has associacion of gene with Cornelia de Lange syndrome, X-linked complex neurodevelopmental disorder, atypical Rett syndrome, Cornelia de Lange syndrome 2, developmental and epileptic encephalopathy, 85, with or without midline brain defects.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.1876C>T	p.Arg626Cys	missense_variant	11/25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.1810C>T	p.Arg604Cys	missense_variant	12/26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.1876C>T	p.Arg626Cys	missense_variant	11/25	1	NM_006306.4	ENSP00000323421	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098156 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363514

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital muscular hypertrophy-cerebral syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMC1A protein function. ClinVar contains an entry for this variant (Variation ID: 532570). This variant has not been reported in the literature in individuals affected with SMC1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 626 of the SMC1A protein (p.Arg626Cys). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	D;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.54
MVP		0.96
MPC		3.3
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.68
gMVP		0.97

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: rs1556889577; hg19: chrX-53432460;