chr19-2427523-C-G

Variant names:

• chr19-2427523-C-G
• rs767793179
• NM_012458.4:c.11G>C

Variant summary

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

The NM_012458.4(TIMM13):​c.11G>C​(p.Gly4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. G4D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TIMM13 NM_012458.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• Publications: 0 publications found

Genes affected

TIMM13 (HGNC:11816): (translocase of inner mitochondrial membrane 13) This gene encodes a member of the evolutionarily conserved TIMM (translocase of inner mitochondrial membrane) family of proteins that function as chaperones in the import of proteins from the cytoplasm into the mitochondrial inner membrane. Proteins of this family play a role in collecting substrate proteins from the translocase of the outer mitochondrial membrane (TOM) complex and delivering them to either the sorting and assembly machinery in the outer mitochondrial membrane (SAM) complex or the TIMM22 complex in the inner mitochondrial membrane. The encoded protein and the translocase of mitochondrial inner membrane 8a protein form a 70 kDa complex in the intermembrane space. [provided by RefSeq, Jul 2013]

LMNB2 (HGNC:6638): (lamin B2) This gene encodes a B type nuclear lamin. The nuclear lamina consists of a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Mutations in this gene are associated with acquired partial lipodystrophy. [provided by RefSeq, May 2012]

LMNB2 Gene-Disease associations (from GenCC):

• microcephaly 27, primary, autosomal dominant

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• progressive myoclonic epilepsy type 9

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• microcephaly

  Inheritance: AD Classification: MODERATE Submitted by: Franklin by Genoox
• lipodystrophy, partial, acquired, susceptibility to

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• central nervous system malformation

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

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=0.10161799).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012458.4. 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
	TIMM13	NM_012458.4	MANE Select	c.11G>C	p.Gly4Ala	missense	Exon 1 of 3	NP_036590.1	Q9Y5L4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM13	ENST00000215570.8	TSL:1 MANE Select	c.11G>C	p.Gly4Ala	missense	Exon 1 of 3	ENSP00000215570.2	Q9Y5L4
	TIMM13	ENST00000853532.1		c.11G>C	p.Gly4Ala	missense	Exon 1 of 3	ENSP00000523591.1
	TIMM13	ENST00000939025.1		c.11G>C	p.Gly4Ala	missense	Exon 1 of 3	ENSP00000609084.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453820 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723012

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 43216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39424

South Asian (SAS) AF: 0.00 AC: 0 AN: 85702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109018

Other (OTH) AF: 0.00 AC: 0 AN: 60020

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.90	T
PhyloP100		1.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0050	B
Vest4		0.14
MutPred		0.096		Gain of catalytic residue at G4 (P = 0.1091)
MVP		0.84
MPC		0.21
ClinPred		0.73	D
GERP RS		3.1
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.071
gMVP		0.56
Mutation Taster		=68/32	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: rs767793179; hg19: chr19-2427521;