rs144850468

Variant names:

• chrX-53409435-G-A
• rs144850468
• NM_006306.4:c.1323C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006306.4(SMC1A):​c.1323C>T​(p.Tyr441Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,204,537 control chromosomes in the GnomAD database, including 2 homozygotes. There are 82 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 0.0017 (1 hom., 39 hem., cov: 22)
  • Exomes 𝑓: 0.00018 (1 hom. 43 hem.)
• Consequence: SMC1A NM_006306.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.643
• Publications: 0 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-53409435-G-A is Benign according to our data. Variant chrX-53409435-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.643 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00165 (184/111383) while in subpopulation AFR AF = 0.00574 (176/30669). AF 95% confidence interval is 0.00505. There are 1 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 184 XL,AD gene.

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.1323C>T	p.Tyr441Tyr	synonymous	Exon 8 of 25	NP_006297.2
	SMC1A	NM_001281463.1		c.1257C>T	p.Tyr419Tyr	synonymous	Exon 9 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.1323C>T	p.Tyr441Tyr	synonymous	Exon 8 of 25	ENSP00000323421.3	Q14683
	SMC1A	ENST00000375340.10	TSL:1	c.1257C>T	p.Tyr419Tyr	synonymous	Exon 9 of 26	ENSP00000364489.7	G8JLG1
	SMC1A	ENST00000675504.1		c.1257C>T	p.Tyr419Tyr	synonymous	Exon 8 of 25	ENSP00000502524.1	G8JLG1

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 184 AN: 111331 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.00575

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000674

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

GnomAD2 exomes AF: 0.000534 AC: 98 AN: 183480 AF XY: 0.000177

Gnomad AFR exome AF: 0.00585

Gnomad AMR exome AF: 0.000693

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.000177 AC: 193 AN: 1093154 Hom.: 1 Cov.: 30 AF XY: 0.000120 AC XY: 43 AN XY: 358726

African (AFR) AF: 0.00566 AC: 149 AN: 26323

American (AMR) AF: 0.000739 AC: 26 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19365

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 837486

Other (OTH) AF: 0.000327 AC: 15 AN: 45910

GnomAD4 genome AF: 0.00165 AC: 184 AN: 111383 Hom.: 1 Cov.: 22 AF XY: 0.00116 AC XY: 39 AN XY: 33561

African (AFR) AF: 0.00574 AC: 176 AN: 30669

American (AMR) AF: 0.000673 AC: 7 AN: 10401

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.00 AC: 0 AN: 2672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53085

Other (OTH) AF: 0.000660 AC: 1 AN: 1516

Alfa AF: 0.00126 Hom.: 9

Bravo AF: 0.00216

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital muscular hypertrophy-cerebral syndrome (1)
-	-	1	Congenital muscular hypertrophy-cerebral syndrome;C5393312:Developmental and epileptic encephalopathy, 85, with or without midline brain defects (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.4
DANN	Benign	0.55
PhyloP100		0.64
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism

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: rs144850468; hg19: chrX-53436366;