X-53409129-T-G

Position:

• chrX-53409129-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_006306.4(SMC1A):​c.1478A>C​(p.Glu493Ala) variant causes a missense change involving the alteration of a 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SMC1A NM_006306.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.99

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 Likely_pathogenic. Variant got 6 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, 0.932
• PP5: Variant X-53409129-T-G is Pathogenic according to our data. Variant chrX-53409129-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 11673.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-53409129-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.1478A>C	p.Glu493Ala	missense_variant	9/25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.1412A>C	p.Glu471Ala	missense_variant	10/26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.1478A>C	p.Glu493Ala	missense_variant	9/25	1	NM_006306.4	ENSP00000323421	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital muscular hypertrophy-cerebral syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.6	D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.62
MutPred		0.80		Gain of MoRF binding (P = 0.0241);.;
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.84
gMVP		0.97

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: rs122454122; hg19: chrX-53436060;