1-19597107-T-A

Variant names:

• chr1-19597107-T-A
• rs146421936
• NM_001032363.4:c.62T>A

Variant summary

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

The NM_001032363.4(MICOS10):​c.62T>A​(p.Ile21Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. I21T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MICOS10 NM_001032363.4 missense, splice_region
• Scores: Splicing: ADA: 0.3632
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.22
• 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]

MICOS10-DT (HGNC:55676): (MICOS10 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.62T>A	p.Ile21Lys	missense splice_region	Exon 1 of 4	NP_001027535.1	Q5TGZ0-1
	MICOS10-NBL1	NM_001204088.2		c.-165T>A		splice_region	Exon 1 of 5	NP_001191017.1
	MICOS10-NBL1	NM_001204089.2		c.-22T>A		splice_region	Exon 1 of 4	NP_001191018.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MICOS10	ENST00000322753.7	TSL:1 MANE Select	c.62T>A	p.Ile21Lys	missense splice_region	Exon 1 of 4	ENSP00000325562.6	Q5TGZ0-1
	MICOS10-NBL1	ENST00000602384.5	TSL:5	n.41T>A		splice_region non_coding_transcript_exon	Exon 1 of 10	ENSP00000473550.1	R4GNA1
	NBL1	ENST00000602662.1	TSL:2	c.-22T>A		splice_region	Exon 1 of 4	ENSP00000473411.1	P41271-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 235926 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1447776 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720258

African (AFR) AF: 0.00 AC: 0 AN: 31894

American (AMR) AF: 0.00 AC: 0 AN: 43078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25678

East Asian (EAS) AF: 0.00 AC: 0 AN: 37432

South Asian (SAS) AF: 0.00 AC: 0 AN: 84914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105984

Other (OTH) AF: 0.00 AC: 0 AN: 59820

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Benign	0.95
DEOGEN2	Benign	0.098	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.96	T
PhyloP100		4.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.40
Sift	Benign	0.056	T
Sift4G	Benign	0.11	T
Polyphen		0.055	B
Vest4		0.67
MutPred		0.42		Loss of stability (P = 0.024)
MVP		0.28
MPC		0.092
ClinPred		0.91	D
GERP RS		5.2
PromoterAI		0.045	Neutral
Varity_R		0.34
gMVP		0.80
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.36
dbscSNV1_RF	Benign	0.68
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: rs146421936; hg19: chr1-19923601;