5-179837731-T-A

Variant names:

• chr5-179837731-T-A
• rs10277
• NM_016175.4:c.692A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016175.4(MRNIP):​c.692A>T​(p.Gln231Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q231R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: MRNIP NM_016175.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.98
• Publications: 76 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08100629).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016175.4. 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.692A>T	p.Gln231Leu	missense	Exon 7 of 7	NP_057259.2	Q6NTE8-1
	SQSTM1	NM_003900.5	MANE Select	c.*1138T>A		3_prime_UTR	Exon 8 of 8	NP_003891.1	Q13501-1
	MRNIP	NM_001017987.3		c.527A>T	p.Gln176Leu	missense	Exon 5 of 5	NP_001017987.1	Q6NTE8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRNIP	ENST00000292586.11	TSL:1 MANE Select	c.692A>T	p.Gln231Leu	missense	Exon 7 of 7	ENSP00000292586.6	Q6NTE8-1
	MRNIP	ENST00000523084.5	TSL:1	c.290A>T	p.Gln97Leu	missense	Exon 6 of 6	ENSP00000429107.1	E5RJC6
	SQSTM1	ENST00000389805.9	TSL:1 MANE Select	c.*1138T>A		3_prime_UTR	Exon 8 of 8	ENSP00000374455.4	Q13501-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 68

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 119389

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0040
DANN	Benign	0.84
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.077	N
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.0	T
PhyloP100		-5.0
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.054
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.031	D
Polyphen		0.0	B
Vest4		0.19
MutPred		0.26		Loss of solvent accessibility (P = 0.0468)
MVP		0.048
MPC		0.089
ClinPred		0.11	T
GERP RS		-5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.093
gMVP		0.073
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs10277; hg19: chr5-179264731;