5-179833232-G-A

Variant names:

• chr5-179833232-G-A
• rs61748794
• NM_003900.5:c.955G>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_003900.5(SQSTM1):​c.955G>A​(p.Glu319Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,588,600 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (48 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (38 hom.)
• Consequence: SQSTM1 NM_003900.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.390
• Publications: 6 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021701753).
• BP6: Variant 5-179833232-G-A is Benign according to our data. Variant chr5-179833232-G-A is described in ClinVar as Benign. ClinVar VariationId is 353165.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 = 0.013 (1985/152286) while in subpopulation AFR AF = 0.0454 (1886/41560). AF 95% confidence interval is 0.0437. There are 48 homozygotes in GnomAd4. There are 929 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003900.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SQSTM1	NM_003900.5	MANE Select	c.955G>A	p.Glu319Lys	missense	Exon 6 of 8	NP_003891.1
	SQSTM1	NM_001142298.2		c.703G>A	p.Glu235Lys	missense	Exon 7 of 9	NP_001135770.1
	SQSTM1	NM_001142299.2		c.703G>A	p.Glu235Lys	missense	Exon 7 of 9	NP_001135771.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SQSTM1	ENST00000389805.9	TSL:1 MANE Select	c.955G>A	p.Glu319Lys	missense	Exon 6 of 8	ENSP00000374455.4
	SQSTM1	ENST00000360718.5	TSL:1	c.703G>A	p.Glu235Lys	missense	Exon 5 of 7	ENSP00000353944.5
	SQSTM1	ENST00000884700.1		c.979G>A	p.Glu327Lys	missense	Exon 6 of 8	ENSP00000554759.1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1982 AN: 152168 Hom.: 47 Cov.: 33

Gnomad AFR AF: 0.0454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

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: 0.000206

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00353 AC: 716 AN: 202832 AF XY: 0.00262

Gnomad AFR exome AF: 0.0525

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.000952

GnomAD4 exome AF: 0.00134 AC: 1928 AN: 1436314 Hom.: 38 Cov.: 36 AF XY: 0.00117 AC XY: 837 AN XY: 712938

African (AFR) AF: 0.0467 AC: 1538 AN: 32952

American (AMR) AF: 0.00280 AC: 114 AN: 40718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25722

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38314

South Asian (SAS) AF: 0.0000476 AC: 4 AN: 84088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47962

Middle Eastern (MID) AF: 0.00434 AC: 22 AN: 5070

European-Non Finnish (NFE) AF: 0.0000862 AC: 95 AN: 1102088

Other (OTH) AF: 0.00259 AC: 154 AN: 59400

GnomAD4 genome AF: 0.0130 AC: 1985 AN: 152286 Hom.: 48 Cov.: 33 AF XY: 0.0125 AC XY: 929 AN XY: 74452

African (AFR) AF: 0.0454 AC: 1886 AN: 41560

American (AMR) AF: 0.00438 AC: 67 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68032

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00551 Hom.: 5

Bravo AF: 0.0143

ESP6500AA AF: 0.0408 AC: 179

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00393 AC: 473

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (1)
-	-	1	Paget disease of bone 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.8
DANN	Benign	0.82
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.39
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.14
Sift	Benign	0.92	T
Sift4G	Benign	0.85	T
Polyphen		0.0070	B
Vest4		0.10
MVP		0.78
MPC		0.15
ClinPred		0.0011	T
GERP RS		-0.72
Varity_R		0.032
gMVP		0.18
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61748794; hg19: chr5-179260232; COSMIC: COSV52972399;