rs587784414

Variant names:

• chrX-53414994-G-C
• rs587784414
• NM_006306.4:c.285C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-53414994-G-C
• chrX-53414994-G-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_006306.4(SMC1A):​c.285C>G​(p.Ala95Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,208,994 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SMC1A NM_006306.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.334
• Publications: 3 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• developmental and epileptic encephalopathy, 85, with or without midline brain defects

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.02).
• BP6: Variant X-53414994-G-C is Benign according to our data. Variant chrX-53414994-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159952.
• BP7: Synonymous conserved (PhyloP=-0.334 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006306.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC1A	NM_006306.4	MANE Select	c.285C>G	p.Ala95Ala	synonymous	Exon 2 of 25	NP_006297.2
	SMC1A	NM_001281463.1		c.219C>G	p.Ala73Ala	synonymous	Exon 3 of 26	NP_001268392.1	G8JLG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC1A	ENST00000322213.9	TSL:1 MANE Select	c.285C>G	p.Ala95Ala	synonymous	Exon 2 of 25	ENSP00000323421.3	Q14683
	SMC1A	ENST00000375340.10	TSL:1	c.219C>G	p.Ala73Ala	synonymous	Exon 3 of 26	ENSP00000364489.7	G8JLG1
	SMC1A	ENST00000675504.1		c.219C>G	p.Ala73Ala	synonymous	Exon 2 of 25	ENSP00000502524.1	G8JLG1

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111259 Hom.: 0 Cov.: 22

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000551 AC: 1 AN: 181586 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097735 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363113

African (AFR) AF: 0.00 AC: 0 AN: 26390

American (AMR) AF: 0.00 AC: 0 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 54082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841879

Other (OTH) AF: 0.00 AC: 0 AN: 46083

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111259 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33441

African (AFR) AF: 0.00 AC: 0 AN: 30595

American (AMR) AF: 0.00 AC: 0 AN: 10402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.00 AC: 0 AN: 2611

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53082

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Congenital muscular hypertrophy-cerebral syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.0
DANN	Benign	0.40
PhyloP100		-0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587784414; hg19: chrX-53441943;