X-53405077-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_006306.4(SMC1A):c.2131C>G(p.Arg711Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R711Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SMC1A NM_006306.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.76

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 9 ACMG points.

• PM1: In a coiled_coil_region (size 275) in uniprot entity SMC1A_HUMAN there are 20 pathogenic changes around while only 5 benign (80%) in NM_006306.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-53405076-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1076799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, SMC1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC1A	NM_006306.4	c.2131C>G	p.Arg711Gly	missense_variant	13/25	ENST00000322213.9
SMC1A	NM_001281463.1	c.2065C>G	p.Arg689Gly	missense_variant	14/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC1A	ENST00000322213.9	c.2131C>G	p.Arg711Gly	missense_variant	13/25	1	NM_006306.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1092488 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 358686

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.7	D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.71		Loss of stability (P = 0.0241);.;
MVP		0.99
MPC		3.2
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.91
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: rs587784409; hg19: chrX-53432009;