rs146216425

Variant names:

• chrX-53380647-G-A
• rs146216425
• NM_006306.4:c.3591C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-53380647-G-A
• chrX-53380647-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006306.4(SMC1A):​c.3591C>T​(p.Ala1197Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,203,511 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 140 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1197A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., 18 hem., cov: 22)
  • Exomes 𝑓: 0.00033 (0 hom. 122 hem.)
• Consequence: SMC1A NM_006306.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.871
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant X-53380647-G-A is Benign according to our data. Variant chrX-53380647-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.871 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000482 (54/111950) while in subpopulation NFE AF = 0.00049 (26/53110). AF 95% confidence interval is 0.000342. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 54 AD,XL 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.3591C>T	p.Ala1197Ala	synonymous	Exon 24 of 25	NP_006297.2
	SMC1A	NM_001281463.1		c.3525C>T	p.Ala1175Ala	synonymous	Exon 25 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.3591C>T	p.Ala1197Ala	synonymous	Exon 24 of 25	ENSP00000323421.3	Q14683
	SMC1A	ENST00000375340.10	TSL:1	c.3525C>T	p.Ala1175Ala	synonymous	Exon 25 of 26	ENSP00000364489.7	G8JLG1
	SMC1A	ENST00000470241.2	TSL:3	c.809C>T	p.Pro270Leu	missense	Exon 6 of 6	ENSP00000476416.1	V9GY57

Frequencies

GnomAD3 genomes AF: 0.000483 AC: 54 AN: 111897 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: 0.00460

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000489

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000800 AC: 146 AN: 182458 AF XY: 0.000672

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: 0.00583

Gnomad NFE exome AF: 0.000601

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000330 AC: 360 AN: 1091561 Hom.: 0 Cov.: 30 AF XY: 0.000341 AC XY: 122 AN XY: 357365

African (AFR) AF: 0.000114 AC: 3 AN: 26284

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19349

East Asian (EAS) AF: 0.00 AC: 0 AN: 30185

South Asian (SAS) AF: 0.00 AC: 0 AN: 53909

European-Finnish (FIN) AF: 0.00480 AC: 194 AN: 40441

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4111

European-Non Finnish (NFE) AF: 0.000179 AC: 150 AN: 836218

Other (OTH) AF: 0.000283 AC: 13 AN: 45891

GnomAD4 genome AF: 0.000482 AC: 54 AN: 111950 Hom.: 0 Cov.: 22 AF XY: 0.000527 AC XY: 18 AN XY: 34132

African (AFR) AF: 0.00 AC: 0 AN: 30886

American (AMR) AF: 0.00 AC: 0 AN: 10596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3530

South Asian (SAS) AF: 0.00 AC: 0 AN: 2683

European-Finnish (FIN) AF: 0.00460 AC: 28 AN: 6081

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000490 AC: 26 AN: 53110

Other (OTH) AF: 0.00 AC: 0 AN: 1519

Alfa AF: 0.000756 Hom.: 3

Bravo AF: 0.000181

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Congenital muscular hypertrophy-cerebral syndrome (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.3
DANN	Benign	0.62
PhyloP100		-0.87
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=93/7	polymorphism (auto)

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: rs146216425; hg19: chrX-53407568;