chrX-53409301-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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]

SMC1A Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• developmental and epileptic encephalopathy, 85, with or without midline brain defects

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cornelia de Lange syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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

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

African (AFR) AF: 0.00668 AC: 174 AN: 26056

American (AMR) AF: 0.0162 AC: 558 AN: 34480

Ashkenazi Jewish (ASJ) AF: 0.0505 AC: 970 AN: 19204

East Asian (EAS) AF: 0.0000997 AC: 3 AN: 30081

South Asian (SAS) AF: 0.0123 AC: 654 AN: 53318

European-Finnish (FIN) AF: 0.0739 AC: 2971 AN: 40187

Middle Eastern (MID) AF: 0.0442 AC: 180 AN: 4074

European-Non Finnish (NFE) AF: 0.0588 AC: 48493 AN: 824934

Other (OTH) AF: 0.0455 AC: 2068 AN: 45440

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

African (AFR) AF: 0.00712 AC: 218 AN: 30635

American (AMR) AF: 0.0212 AC: 221 AN: 10426

Ashkenazi Jewish (ASJ) AF: 0.0538 AC: 142 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3552

South Asian (SAS) AF: 0.0137 AC: 36 AN: 2622

European-Finnish (FIN) AF: 0.0637 AC: 373 AN: 5851

Middle Eastern (MID) AF: 0.0651 AC: 14 AN: 215

European-Non Finnish (NFE) AF: 0.0584 AC: 3090 AN: 52955

Other (OTH) AF: 0.0366 AC: 55 AN: 1501

Alfa AF: 0.0421 Hom.: 2066

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
PhyloP100		0.43

Splicing

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

Other links and lift over

dbSNP: rs1264008; hg19: chrX-53436232;