rs28997583

Variant names:

• chrX-53380142-G-A
• rs28997583
• NM_006306.4:c.3663C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-53380142-G-A
• chrX-53380142-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006306.4(SMC1A):​c.3663C>T​(p.Thr1221Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,206,337 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000024 (0 hom. 6 hem.)
• Consequence: SMC1A NM_006306.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.81

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant X-53380142-G-A is Benign according to our data. Variant chrX-53380142-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 463886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.81 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000237 (26/1095650) while in subpopulation AMR AF= 0.000597 (21/35195). AF 95% confidence interval is 0.000399. There are 0 homozygotes in gnomad4_exome. There are 6 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.3663C>T	p.Thr1221Thr	synonymous_variant	Exon 25 of 25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.3597C>T	p.Thr1199Thr	synonymous_variant	Exon 26 of 26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.3663C>T	p.Thr1221Thr	synonymous_variant	Exon 25 of 25	1	NM_006306.4	ENSP00000323421.3
SMC1A	ENST00000375340.10	c.3597C>T	p.Thr1199Thr	synonymous_variant	Exon 26 of 26	1		ENSP00000364489.7
SMC1A	ENST00000675504.1	c.3597C>T	p.Thr1199Thr	synonymous_variant	Exon 25 of 25			ENSP00000502524.1
SMC1A	ENST00000674590.1	c.2895C>T	p.Thr965Thr	synonymous_variant	Exon 23 of 23			ENSP00000502626.1

Frequencies

GnomAD3 genomes AF: 0.00000903 AC: 1 AN: 110687 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 32893

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000668

GnomAD3 exomes AF: 0.000116 AC: 21 AN: 180454 Hom.: 0 AF XY: 0.0000606 AC XY: 4 AN XY: 65982

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000731

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000237 AC: 26 AN: 1095650 Hom.: 0 Cov.: 28 AF XY: 0.0000166 AC XY: 6 AN XY: 361246

Gnomad4 AFR exome AF: 0.0000759

Gnomad4 AMR exome AF: 0.000597

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: 0.00000119

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome AF: 0.00000903 AC: 1 AN: 110687 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 32893

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000668

Bravo AF: 0.0000340

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital muscular hypertrophy-cerebral syndrome Benign:1

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 02, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.7
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs28997583; hg19: chrX-53407063;