X-53409301-T-G

Variant names:

• chrX-53409301-T-G
• rs1264008
• NM_006306.4:c.1338-32A>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006306.4(SMC1A):​c.1338-32A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 1,188,849 control chromosomes in the GnomAD database, including 1,282 homozygotes. There are 18,867 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.038 (80 hom., 1163 hem., cov: 22)
  • Exomes 𝑓: 0.052 (1202 hom. 17704 hem.)
• Consequence: SMC1A NM_006306.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.427

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.1338-32A>C		intron_variant	Intron 8 of 24	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.1272-32A>C		intron_variant	Intron 9 of 25		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.1338-32A>C		intron_variant	Intron 8 of 24	1	NM_006306.4	ENSP00000323421.3

Frequencies

GnomAD3 genomes AF: 0.0376 AC: 4172 AN: 111022 Hom.: 80 Cov.: 22 AF XY: 0.0350 AC XY: 1161 AN XY: 33210

Gnomad AFR AF: 0.00713

Gnomad AMI AF: 0.0353

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.0538

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0125

Gnomad FIN AF: 0.0637

Gnomad MID AF: 0.0636

Gnomad NFE AF: 0.0584

Gnomad OTH AF: 0.0371

GnomAD4 exome AF: 0.0520 AC: 56071 AN: 1077774 Hom.: 1202 Cov.: 28 AF XY: 0.0514 AC XY: 17704 AN XY: 344676

Gnomad4 AFR exome AF: 0.00668

Gnomad4 AMR exome AF: 0.0162

Gnomad4 ASJ exome AF: 0.0505

Gnomad4 EAS exome AF: 0.0000997

Gnomad4 SAS exome AF: 0.0123

Gnomad4 FIN exome AF: 0.0739

Gnomad4 NFE exome AF: 0.0588

Gnomad4 OTH exome AF: 0.0455

GnomAD4 genome AF: 0.0376 AC: 4173 AN: 111075 Hom.: 80 Cov.: 22 AF XY: 0.0350 AC XY: 1163 AN XY: 33273

Gnomad4 AFR AF: 0.00712

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.0538

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.0637

Gnomad4 NFE AF: 0.0584

Gnomad4 OTH AF: 0.0366

Alfa AF: 0.0483 Hom.: 1377

Bravo AF: 0.0341

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1264008; hg19: chrX-53436232;