NM_001032363.4:c.220A>C

Variant names:

• chr1-19623581-A-C
• rs748980812
• NM_001032363.4:c.220A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001032363.4(MICOS10):​c.220A>C​(p.Lys74Gln) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K74R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MICOS10 NM_001032363.4 missense, splice_region
• Scores: Splicing: ADA: 0.7354
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.59
• Publications: 0 publications found

Genes affected

MICOS10 (HGNC:32068): (mitochondrial contact site and cristae organizing system subunit 10) Predicted to be involved in inner mitochondrial membrane organization. Located in mitochondrion. Part of MIB complex; MICOS complex; and SAM complex. [provided by Alliance of Genome Resources, Apr 2022]

MICOS10-NBL1 (HGNC:48338): (MICOS10-NBL1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring chromosome 1 open reading frame 151 (GeneID 440574) and neuroblastoma suppressor of tumorigenicity 1 (GeneID 4681) genes on chromosome 1. The read-through transcripts produce at least two proteins, each of which share identity with proteins translated from the downstream neuroblastoma suppressor of tumorigenicity 1 locus. [provided by RefSeq, Feb 2011]

NBL1 (HGNC:7650): (NBL1, DAN family BMP antagonist) This gene product is the founding member of the evolutionarily conserved CAN (Cerberus and DAN) family of proteins, which contain a domain resembling the CTCK (C-terminal cystine knot-like) motif found in a number of signaling molecules. These proteins are secreted, and act as BMP (bone morphogenetic protein) antagonists by binding to BMPs and preventing them from interacting with their receptors. They may thus play an important role during growth and development. Alternatively spliced transcript variants have been identified for this gene. Read-through transcripts between this locus and the upstream mitochondrial inner membrane organizing system 1 gene (GeneID 440574) have been observed. [provided by RefSeq, May 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3868224).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032363.4. 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
	MICOS10	NM_001032363.4	MANE Select	c.220A>C	p.Lys74Gln	missense splice_region	Exon 3 of 4	NP_001027535.1	Q5TGZ0-1
	MICOS10	NM_001204083.2		c.220A>C	p.Lys74Gln	missense splice_region	Exon 3 of 5	NP_001191012.1
	MICOS10	NM_001204082.2		c.172A>C	p.Lys58Gln	missense splice_region	Exon 2 of 3	NP_001191011.1	A0A087WU07

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MICOS10	ENST00000322753.7	TSL:1 MANE Select	c.220A>C	p.Lys74Gln	missense splice_region	Exon 3 of 4	ENSP00000325562.6	Q5TGZ0-1
	MICOS10-NBL1	ENST00000602384.5	TSL:5	n.199A>C		splice_region non_coding_transcript_exon	Exon 3 of 10	ENSP00000473550.1	R4GNA1
	MICOS10	ENST00000617872.4	TSL:2	c.172A>C	p.Lys58Gln	missense splice_region	Exon 2 of 3	ENSP00000478278.1	A0A087WU07

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.0030	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.99	T
PhyloP100		6.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.17
Sift	Benign	0.21	T
Sift4G	Benign	0.20	T
Polyphen		0.95	P
Vest4		0.48
MutPred		0.19		Loss of ubiquitination at K74 (P = 0.0107)
MVP		0.57
MPC		0.17
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.68
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.74
dbscSNV1_RF	Benign	0.54
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: rs748980812; hg19: chr1-19950075;