X-53422619-G-A

Variant names:

• chrX-53422619-G-A
• rs1264011
• NM_006306.4:c.-19C>T

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.-19C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 112,256 control chromosomes in the GnomAD database, including 9,273 homozygotes. There are 14,999 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (9273 hom., 14999 hem., cov: 25)
  • Exomes 𝑓: 0.57 (115090 hom. 174600 hem.)
  • Failed GnomAD Quality Control
• Consequence: SMC1A NM_006306.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.251
• Publications: 16 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]

RIBC1 (HGNC:26537): (RIB43A domain with coiled-coils 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant X-53422619-G-A is Benign according to our data. Variant chrX-53422619-G-A is described in ClinVar as [Benign]. Clinvar id is 95364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.-19C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 25	ENST00000322213.9	NP_006297.2
SMC1A	NM_006306.4	c.-19C>T		5_prime_UTR_variant	Exon 1 of 25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.-231C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 26		NP_001268392.1
SMC1A	NM_001281463.1	c.-231C>T		5_prime_UTR_variant	Exon 1 of 26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.-19C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 25	1	NM_006306.4	ENSP00000323421.3
SMC1A	ENST00000322213.9	c.-19C>T		5_prime_UTR_variant	Exon 1 of 25	1	NM_006306.4	ENSP00000323421.3

Frequencies

GnomAD3 genomes AF: 0.435 AC: 48816 AN: 112202 Hom.: 9278 Cov.: 25

Gnomad AFR AF: 0.0885

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.528

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.607

Gnomad MID AF: 0.553

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.462

GnomAD2 exomes AF: 0.523 AC: 94446 AN: 180723 AF XY: 0.532

Gnomad AFR exome AF: 0.0779

Gnomad AMR exome AF: 0.522

Gnomad ASJ exome AF: 0.490

Gnomad EAS exome AF: 0.534

Gnomad FIN exome AF: 0.601

Gnomad NFE exome AF: 0.593

Gnomad OTH exome AF: 0.550

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.573 AC: 572950 AN: 1000785 Hom.: 115090 Cov.: 18 AF XY: 0.595 AC XY: 174600 AN XY: 293349

African (AFR) AF: 0.0789 AC: 1900 AN: 24077

American (AMR) AF: 0.518 AC: 18098 AN: 34916

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 9385 AN: 18716

East Asian (EAS) AF: 0.505 AC: 14955 AN: 29623

South Asian (SAS) AF: 0.470 AC: 24388 AN: 51843

European-Finnish (FIN) AF: 0.607 AC: 23863 AN: 39332

Middle Eastern (MID) AF: 0.608 AC: 2389 AN: 3931

European-Non Finnish (NFE) AF: 0.602 AC: 454645 AN: 755548

Other (OTH) AF: 0.545 AC: 23327 AN: 42799

GnomAD4 genome AF: 0.435 AC: 48818 AN: 112256 Hom.: 9273 Cov.: 25 AF XY: 0.435 AC XY: 14999 AN XY: 34476

African (AFR) AF: 0.0884 AC: 2753 AN: 31138

American (AMR) AF: 0.506 AC: 5421 AN: 10723

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1340 AN: 2656

East Asian (EAS) AF: 0.529 AC: 1841 AN: 3483

South Asian (SAS) AF: 0.437 AC: 1203 AN: 2756

European-Finnish (FIN) AF: 0.607 AC: 3664 AN: 6041

Middle Eastern (MID) AF: 0.565 AC: 121 AN: 214

European-Non Finnish (NFE) AF: 0.592 AC: 31414 AN: 53045

Other (OTH) AF: 0.460 AC: 701 AN: 1523

Alfa AF: 0.509 Hom.: 6264

Bravo AF: 0.417

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 38% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 35. Only high quality variants are reported. -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Developmental and epileptic encephalopathy, 85, with or without midline brain defects Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital muscular hypertrophy-cerebral syndrome Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

De Lange syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.2
DANN	Benign	0.93
PhyloP100		0.25
PromoterAI		0.00040	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.1
Mutation Taster		=300/0	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: rs1264011; hg19: chrX-53449568; COSMIC: COSV59127562; COSMIC: COSV59127562;