rs248244

Variant names:

• chr5-179838216-C-T
• rs248244
• ENST00000518219.5:c.*2614G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000518219.5(MRNIP):​c.*2614G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 360,462 control chromosomes in the GnomAD database, including 626 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.061 (318 hom., cov: 33)
  • Exomes 𝑓: 0.048 (308 hom.)
• Consequence: MRNIP ENST00000518219.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.164
• Publications: 4 publications found

Genes affected

MRNIP (HGNC:30817): (MRN complex interacting protein) Enables chromatin binding activity. Involved in several processes, including mitotic G2 DNA damage checkpoint signaling; regulation of double-strand break repair; and response to ionizing radiation. Located in nucleoplasm. Colocalizes with Mre11 complex. [provided by Alliance of Genome Resources, Apr 2022]

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0819 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000518219.5. 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
	MRNIP	NM_016175.4	MANE Select	c.538-331G>A		intron	N/A	NP_057259.2	Q6NTE8-1
	MRNIP	NM_001017987.3		c.373-331G>A		intron	N/A	NP_001017987.1	Q6NTE8-3
	SQSTM1	NM_003900.5	MANE Select	c.*1623C>T		downstream_gene	N/A	NP_003891.1	Q13501-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRNIP	ENST00000518219.5	TSL:1	c.*2614G>A		3_prime_UTR	Exon 6 of 6	ENSP00000428460.1	E5RI52
	MRNIP	ENST00000292586.11	TSL:1 MANE Select	c.538-331G>A		intron	N/A	ENSP00000292586.6	Q6NTE8-1
	MRNIP	ENST00000523084.5	TSL:1	c.136-331G>A		intron	N/A	ENSP00000429107.1	E5RJC6

Frequencies

GnomAD3 genomes AF: 0.0614 AC: 9348 AN: 152138 Hom.: 318 Cov.: 33

Gnomad AFR AF: 0.0843

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.0626

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0524

Gnomad OTH AF: 0.0644

GnomAD4 exome AF: 0.0477 AC: 9936 AN: 208206 Hom.: 308 Cov.: 0 AF XY: 0.0461 AC XY: 5005 AN XY: 108596

African (AFR) AF: 0.0852 AC: 635 AN: 7452

American (AMR) AF: 0.0434 AC: 380 AN: 8758

Ashkenazi Jewish (ASJ) AF: 0.0928 AC: 590 AN: 6358

East Asian (EAS) AF: 0.0000807 AC: 1 AN: 12390

South Asian (SAS) AF: 0.0239 AC: 573 AN: 24016

European-Finnish (FIN) AF: 0.0402 AC: 432 AN: 10752

Middle Eastern (MID) AF: 0.0996 AC: 91 AN: 914

European-Non Finnish (NFE) AF: 0.0524 AC: 6592 AN: 125802

Other (OTH) AF: 0.0546 AC: 642 AN: 11764

GnomAD4 genome AF: 0.0614 AC: 9349 AN: 152256 Hom.: 318 Cov.: 33 AF XY: 0.0599 AC XY: 4459 AN XY: 74448

African (AFR) AF: 0.0842 AC: 3498 AN: 41538

American (AMR) AF: 0.0626 AC: 958 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3470

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0282 AC: 136 AN: 4828

European-Finnish (FIN) AF: 0.0465 AC: 493 AN: 10600

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0524 AC: 3562 AN: 68026

Other (OTH) AF: 0.0627 AC: 132 AN: 2104

Alfa AF: 0.0561 Hom.: 219

Bravo AF: 0.0630

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.64
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

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: rs248244; hg19: chr5-179265216;