chr5-179820718-G-A

Variant names:

• chr5-179820718-G-A
• rs73351637
• NM_001142298.2:c.-47-2240G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001142298.2(SQSTM1):​c.-47-2240G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 468,444 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (35 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: SQSTM1 NM_001142298.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.808
• Publications: 0 publications found

Genes affected

SQSTM1 (HGNC:11280): (sequestosome 1) This gene encodes a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene. Mutations in this gene result in sporadic and familial Paget disease of bone. [provided by RefSeq, Mar 2009]

SQSTM1 Gene-Disease associations (from GenCC):

• neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• osteosarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Paget disease of bone 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• behavioral variant of frontotemporal dementia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• frontotemporal dementia with motor neuron disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000301422 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 5-179820718-G-A is Benign according to our data. Variant chr5-179820718-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1211577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1548/150350) while in subpopulation AFR AF = 0.035 (1450/41450). AF 95% confidence interval is 0.0335. There are 35 homozygotes in GnomAd4. There are 726 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_001142298.2	c.-47-2240G>A		intron_variant	Intron 2 of 8		NP_001135770.1
SQSTM1	NM_001142299.2	c.-47-2240G>A		intron_variant	Intron 2 of 8		NP_001135771.1
SQSTM1	NM_003900.5	c.-219G>A		upstream_gene_variant		ENST00000389805.9	NP_003891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.-219G>A		upstream_gene_variant		1	NM_003900.5	ENSP00000374455.4

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1543 AN: 150230 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.0350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00395

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.000270

Gnomad OTH AF: 0.00919

GnomAD4 exome AF: 0.00115 AC: 365 AN: 318094 Hom.: 5 Cov.: 4 AF XY: 0.000980 AC XY: 163 AN XY: 166316

African (AFR) AF: 0.0291 AC: 209 AN: 7194

American (AMR) AF: 0.00432 AC: 32 AN: 7400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10222

East Asian (EAS) AF: 0.00 AC: 0 AN: 22574

South Asian (SAS) AF: 0.0000853 AC: 2 AN: 23446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25714

Middle Eastern (MID) AF: 0.0110 AC: 17 AN: 1540

European-Non Finnish (NFE) AF: 0.000234 AC: 47 AN: 200570

Other (OTH) AF: 0.00298 AC: 58 AN: 19434

GnomAD4 genome AF: 0.0103 AC: 1548 AN: 150350 Hom.: 35 Cov.: 33 AF XY: 0.00987 AC XY: 726 AN XY: 73548

African (AFR) AF: 0.0350 AC: 1450 AN: 41450

American (AMR) AF: 0.00394 AC: 60 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10402

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.000270 AC: 18 AN: 66664

Other (OTH) AF: 0.00909 AC: 19 AN: 2090

Alfa AF: 0.00853 Hom.: 3

Bravo AF: 0.0111

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 21, 2019

GeneDx

Significance: Likely 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	-0.59
CADD	Benign	6.7
DANN	Benign	0.96
PhyloP100		0.81
PromoterAI		-0.030	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs73351637; hg19: chr5-179247718;