rs2297104

Variant names:

• chrX-53403898-A-G
• rs2297104
• NM_006306.4:c.2197-5T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006306.4(SMC1A):​c.2197-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00826 in 1,160,911 control chromosomes in the GnomAD database, including 344 homozygotes. There are 2,792 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (30 hom., 338 hem., cov: 22)
  • Exomes 𝑓: 0.0081 (314 hom. 2454 hem.)
• Consequence: SMC1A NM_006306.4 splice_region, intron
• Scores: Splicing: ADA: 0.0008819
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 3.23
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant X-53403898-A-G is Benign according to our data. Variant chrX-53403898-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0665 is higher than 0.05.

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.2197-5T>C		splice_region intron	N/A	NP_006297.2
	SMC1A	NM_001281463.1		c.2131-5T>C		splice_region intron	N/A	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.2197-5T>C		splice_region intron	N/A	ENSP00000323421.3	Q14683
	SMC1A	ENST00000375340.10	TSL:1	c.2131-5T>C		splice_region intron	N/A	ENSP00000364489.7	G8JLG1
	SMC1A	ENST00000675504.1		c.2131-5T>C		splice_region intron	N/A	ENSP00000502524.1	G8JLG1

Frequencies

GnomAD3 genomes AF: 0.00984 AC: 1100 AN: 111811 Hom.: 31 Cov.: 22

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.0162

Gnomad EAS AF: 0.0742

Gnomad SAS AF: 0.00440

Gnomad FIN AF: 0.000996

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000826

Gnomad OTH AF: 0.0188

GnomAD2 exomes AF: 0.0249 AC: 4560 AN: 183248 AF XY: 0.0181

Gnomad AFR exome AF: 0.00433

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.0677

Gnomad FIN exome AF: 0.00132

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.0161

GnomAD4 exome AF: 0.00809 AC: 8484 AN: 1049047 Hom.: 314 Cov.: 26 AF XY: 0.00769 AC XY: 2454 AN XY: 319309

African (AFR) AF: 0.00243 AC: 62 AN: 25533

American (AMR) AF: 0.111 AC: 3883 AN: 35134

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 247 AN: 19097

East Asian (EAS) AF: 0.0986 AC: 2960 AN: 30024

South Asian (SAS) AF: 0.00466 AC: 247 AN: 52996

European-Finnish (FIN) AF: 0.00141 AC: 57 AN: 40516

Middle Eastern (MID) AF: 0.000250 AC: 1 AN: 4003

European-Non Finnish (NFE) AF: 0.000600 AC: 478 AN: 797207

Other (OTH) AF: 0.0123 AC: 549 AN: 44537

GnomAD4 genome AF: 0.00983 AC: 1100 AN: 111864 Hom.: 30 Cov.: 22 AF XY: 0.00993 AC XY: 338 AN XY: 34036

African (AFR) AF: 0.00431 AC: 133 AN: 30849

American (AMR) AF: 0.0549 AC: 573 AN: 10437

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 43 AN: 2654

East Asian (EAS) AF: 0.0739 AC: 261 AN: 3534

South Asian (SAS) AF: 0.00368 AC: 10 AN: 2717

European-Finnish (FIN) AF: 0.000996 AC: 6 AN: 6024

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.000826 AC: 44 AN: 53239

Other (OTH) AF: 0.0192 AC: 29 AN: 1508

Alfa AF: 0.00860 Hom.: 65

Bravo AF: 0.0158

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	1	Congenital muscular hypertrophy-cerebral syndrome (1)
-	-	1	De Lange syndrome (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		3.2
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00088
dbscSNV1_RF	Benign	0.098
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: rs2297104; hg19: chrX-53430830; COSMIC: COSV59132427;