3-128064855-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013336.4(SEC61A1):c.617-22A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,563,452 control chromosomes in the GnomAD database, including 44,364 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4128 hom., cov: 33)
  • Exomes 𝑓: 0.23 (40236 hom.)
• Consequence: SEC61A1 NM_013336.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.37

Genes affected

SEC61A1 (HGNC:18276): (SEC61 translocon subunit alpha 1) The protein encoded by this gene belongs to the SECY/SEC61- alpha family. It appears to play a crucial role in the insertion of secretory and membrane polypeptides into the endoplasmic reticulum. This protein found to be tightly associated with membrane-bound ribosomes, either directly or through adaptor proteins. This gene encodes an alpha subunit of the heteromeric SEC61 complex, which also contains beta and gamma subunits. [provided by RefSeq, Jul 2008]

RUVBL1 (HGNC:10474): (RuvB like AAA ATPase 1) This gene encodes a protein that has both DNA-dependent ATPase and DNA helicase activities and belongs to the ATPases associated with diverse cellular activities (AAA+) protein family. The encoded protein associates with several multisubunit transcriptional complexes and with protein complexes involved in both ATP-dependent remodeling and histone modification. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 3-128064855-A-T is Benign according to our data. Variant chr3-128064855-A-T is described in ClinVar as [Benign]. Clinvar id is 1183327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC61A1	NM_013336.4	c.617-22A>T		intron_variant		ENST00000243253.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC61A1	ENST00000243253.8	c.617-22A>T		intron_variant		1	NM_013336.4	P4

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35150 AN: 152010 Hom.: 4128 Cov.: 33

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.0842

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.226

GnomAD3 exomes AF: 0.220 AC: 47312 AN: 215110 Hom.: 5546 AF XY: 0.225 AC XY: 25791 AN XY: 114728

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.0833

Gnomad SAS exome AF: 0.260

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.236

GnomAD4 exome AF: 0.235 AC: 331156 AN: 1411324 Hom.: 40236 Cov.: 31 AF XY: 0.236 AC XY: 164137 AN XY: 696748

Gnomad4 AFR exome AF: 0.241

Gnomad4 AMR exome AF: 0.136

Gnomad4 ASJ exome AF: 0.273

Gnomad4 EAS exome AF: 0.0742

Gnomad4 SAS exome AF: 0.264

Gnomad4 FIN exome AF: 0.272

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.237

GnomAD4 genome AF: 0.231 AC: 35154 AN: 152128 Hom.: 4128 Cov.: 33 AF XY: 0.232 AC XY: 17220 AN XY: 74364

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.267

Gnomad4 EAS AF: 0.0844

Gnomad4 SAS AF: 0.273

Gnomad4 FIN AF: 0.262

Gnomad4 NFE AF: 0.244

Gnomad4 OTH AF: 0.228

Alfa AF: 0.236 Hom.: 834

Bravo AF: 0.222

Asia WGS AF: 0.183 AC: 641 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 41% of patients studied by a panel of primary immunodeficiencies. Number of patients: 39. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.17
Dann	Benign	0.74

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: rs1044843; hg19: chr3-127783698; COSMIC: COSV54576807; COSMIC: COSV54576807;