chrX-53399695-A-C

Variant names:

• chrX-53399695-A-C
• rs587784413
• NM_006306.4:c.2456T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP6

The NM_006306.4(SMC1A):​c.2456T>G​(p.Ile819Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SMC1A NM_006306.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 9.12

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.

• PM1: In a coiled_coil_region (size 275) in uniprot entity SMC1A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006306.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMC1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 68 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 6.4479 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• BP6: Variant X-53399695-A-C is Benign according to our data. Variant chrX-53399695-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159951.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.2456T>G	p.Ile819Ser	missense_variant	Exon 16 of 25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.2390T>G	p.Ile797Ser	missense_variant	Exon 17 of 26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.2456T>G	p.Ile819Ser	missense_variant	Exon 16 of 25	1	NM_006306.4	ENSP00000323421.3
SMC1A	ENST00000375340.10	c.2390T>G	p.Ile797Ser	missense_variant	Exon 17 of 26	1		ENSP00000364489.7
SMC1A	ENST00000675504.1	c.2390T>G	p.Ile797Ser	missense_variant	Exon 16 of 25			ENSP00000502524.1
SMC1A	ENST00000674590.1	c.1688T>G	p.Ile563Ser	missense_variant	Exon 14 of 23			ENSP00000502626.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital muscular hypertrophy-cerebral syndrome Uncertain:1

Jan 13, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SMC1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 159951). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with serine at codon 819 of the SMC1A protein (p.Ile819Ser). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and serine. -

not specified Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.1	N;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	1.3	N;.
REVEL	Uncertain	0.42
Sift	Benign	0.27	T;.
Sift4G	Benign	0.78	T;T
Polyphen		0.012	B;.
Vest4		0.75
MutPred		0.45		Gain of phosphorylation at I819 (P = 0.0233);.;
MVP		1.0
MPC		2.0
ClinPred		0.65	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.82

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: rs587784413; hg19: chrX-53426617;