chrX-53405804-C-T

Variant names:

• chrX-53405804-C-T
• rs7052858
• NM_006306.4:c.1698G>A

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.1698G>A​(p.Glu566Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,208,741 control chromosomes in the GnomAD database, including 9 homozygotes. There are 249 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 0.0041 (5 hom., 127 hem., cov: 23)
  • Exomes 𝑓: 0.00045 (4 hom. 122 hem.)
• Consequence: SMC1A NM_006306.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.585
• 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]

MIR6857 (HGNC:50263): (microRNA 6857) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-53405804-C-T is Benign according to our data. Variant chrX-53405804-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.585 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00415 (461/111187) while in subpopulation AFR AF = 0.0146 (447/30522). AF 95% confidence interval is 0.0135. There are 5 homozygotes in GnomAd4. There are 127 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 461 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.1698G>A	p.Glu566Glu	synonymous	Exon 10 of 25	NP_006297.2
	SMC1A	NM_001281463.1		c.1632G>A	p.Glu544Glu	synonymous	Exon 11 of 26	NP_001268392.1	G8JLG1
	MIR6857	NR_106916.1		n.-39G>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC1A	ENST00000322213.9	TSL:1 MANE Select	c.1698G>A	p.Glu566Glu	synonymous	Exon 10 of 25	ENSP00000323421.3	Q14683
	SMC1A	ENST00000375340.10	TSL:1	c.1632G>A	p.Glu544Glu	synonymous	Exon 11 of 26	ENSP00000364489.7	G8JLG1
	SMC1A	ENST00000675504.1		c.1632G>A	p.Glu544Glu	synonymous	Exon 10 of 25	ENSP00000502524.1	G8JLG1

Frequencies

GnomAD3 genomes AF: 0.00416 AC: 462 AN: 111135 Hom.: 5 Cov.: 23

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000673

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000760

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00266

GnomAD2 exomes AF: 0.00125 AC: 227 AN: 181322 AF XY: 0.000713

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.000770

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: 0.000668

GnomAD4 exome AF: 0.000447 AC: 491 AN: 1097554 Hom.: 4 Cov.: 32 AF XY: 0.000336 AC XY: 122 AN XY: 362924

African (AFR) AF: 0.0163 AC: 429 AN: 26398

American (AMR) AF: 0.000711 AC: 25 AN: 35142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30187

South Asian (SAS) AF: 0.00 AC: 0 AN: 54024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40497

Middle Eastern (MID) AF: 0.000726 AC: 3 AN: 4131

European-Non Finnish (NFE) AF: 0.00000594 AC: 5 AN: 841727

Other (OTH) AF: 0.000629 AC: 29 AN: 46076

GnomAD4 genome AF: 0.00415 AC: 461 AN: 111187 Hom.: 5 Cov.: 23 AF XY: 0.00381 AC XY: 127 AN XY: 33369

African (AFR) AF: 0.0146 AC: 447 AN: 30522

American (AMR) AF: 0.000672 AC: 7 AN: 10416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3519

South Asian (SAS) AF: 0.000762 AC: 2 AN: 2623

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5985

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

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53053

Other (OTH) AF: 0.00263 AC: 4 AN: 1522

Alfa AF: 0.00228 Hom.: 13

Bravo AF: 0.00488

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)
-	-	2	not provided (2)
-	-	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	-0.49
CADD	Benign	8.7
DANN	Benign	0.51
PhyloP100		0.58
Mutation Taster		=99/1	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: rs7052858; hg19: chrX-53432736;