NM_003900.5:c.183C>T

Variant names:

• chr5-179821119-C-T
• rs767340839
• NM_003900.5:c.183C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003900.5(SQSTM1):​c.183C>T​(p.Gly61Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,380,634 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G61G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0037 (10 hom.)
• Consequence: SQSTM1 NM_003900.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.49
• Publications: 3 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: Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3

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

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

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 5-179821119-C-T is Benign according to our data. Variant chr5-179821119-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 353157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00289 (440/152000) while in subpopulation NFE AF = 0.00449 (305/67912). AF 95% confidence interval is 0.00408. There are 0 homozygotes in GnomAd4. There are 234 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SQSTM1	NM_003900.5	MANE Select	c.183C>T	p.Gly61Gly	synonymous	Exon 1 of 8	NP_003891.1	Q13501-1
	SQSTM1	NM_001142298.2		c.-47-1839C>T		intron	N/A	NP_001135770.1	Q13501-2
	SQSTM1	NM_001142299.2		c.-47-1839C>T		intron	N/A	NP_001135771.1	Q13501-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SQSTM1	ENST00000389805.9	TSL:1 MANE Select	c.183C>T	p.Gly61Gly	synonymous	Exon 1 of 8	ENSP00000374455.4	Q13501-1
	SQSTM1	ENST00000884700.1		c.183C>T	p.Gly61Gly	synonymous	Exon 1 of 8	ENSP00000554759.1
	SQSTM1	ENST00000884698.1		c.183C>T	p.Gly61Gly	synonymous	Exon 1 of 8	ENSP00000554757.1

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 440 AN: 151892 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00520

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00870

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00449

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00432 AC: 110 AN: 25480 AF XY: 0.00449

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000250

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.00507

Gnomad OTH exome AF: 0.00272

GnomAD4 exome AF: 0.00373 AC: 4588 AN: 1228634 Hom.: 10 Cov.: 31 AF XY: 0.00374 AC XY: 2231 AN XY: 596978

African (AFR) AF: 0.000284 AC: 7 AN: 24646

American (AMR) AF: 0.000572 AC: 8 AN: 13992

Ashkenazi Jewish (ASJ) AF: 0.00556 AC: 103 AN: 18520

East Asian (EAS) AF: 0.00 AC: 0 AN: 27166

South Asian (SAS) AF: 0.00157 AC: 89 AN: 56666

European-Finnish (FIN) AF: 0.00720 AC: 219 AN: 30414

Middle Eastern (MID) AF: 0.000548 AC: 2 AN: 3650

European-Non Finnish (NFE) AF: 0.00398 AC: 3988 AN: 1003010

Other (OTH) AF: 0.00340 AC: 172 AN: 50570

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152000 Hom.: 0 Cov.: 34 AF XY: 0.00315 AC XY: 234 AN XY: 74302

African (AFR) AF: 0.000410 AC: 17 AN: 41486

American (AMR) AF: 0.000196 AC: 3 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00520 AC: 18 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4814

European-Finnish (FIN) AF: 0.00870 AC: 92 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00449 AC: 305 AN: 67912

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00396 Hom.: 1

Bravo AF: 0.00206

Asia WGS AF: 0.000580 AC: 2 AN: 3462

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.94
PhyloP100		-1.5
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0
Mutation Taster		=100/0	polymorphism

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: rs767340839; hg19: chr5-179248119;