rs144850468

chrX-53409435-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006306.4(SMC1A):c.1323C>T(p.Tyr441=) 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:5
• Conservation: PhyloP100: 0.643

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 198840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53409435-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 39 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC1A	NM_006306.4	c.1323C>T	p.Tyr441=	synonymous_variant	8/25	ENST00000322213.9
SMC1A	NM_001281463.1	c.1257C>T	p.Tyr419=	synonymous_variant	9/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC1A	ENST00000322213.9	c.1323C>T	p.Tyr441=	synonymous_variant	8/25	1	NM_006306.4	P1

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 184 AN: 111331 Hom.: 1 Cov.: 22 AF XY: 0.00116 AC XY: 39 AN XY: 33499

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

GnomAD3 exomes AF: 0.000534 AC: 98 AN: 183480 Hom.: 0 AF XY: 0.000177 AC XY: 12 AN XY: 67920

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 SAS 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

Gnomad4 AFR exome AF: 0.00566

Gnomad4 AMR exome AF: 0.000739

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000239

Gnomad4 OTH exome AF: 0.000327

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

Gnomad4 AFR AF: 0.00574

Gnomad4 AMR AF: 0.000673

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000660

Alfa AF: 0.00126 Hom.: 9

Bravo AF: 0.00216

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 18, 2015

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Congenital muscular hypertrophy-cerebral syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2020

- -

Congenital muscular hypertrophy-cerebral syndrome;C5393312:Developmental and epileptic encephalopathy, 85, with or without midline brain defects Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	5.4
Dann	Benign	0.55
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs144850468; hg19: chrX-53436366;