chr3-158670991-T-C

Variant names:

• chr3-158670991-T-C
• rs8455
• NM_020169.4:c.158A>G

Variant summary

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

The NM_020169.4(LXN):​c.158A>G​(p.His53Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 1,522,880 control chromosomes in the GnomAD database, including 217,212 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.57 (25840 hom., cov: 33)
  • Exomes 𝑓: 0.52 (191372 hom.)
• Consequence: LXN NM_020169.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.154
• Publications: 50 publications found

Genes affected

LXN (HGNC:13347): (latexin) This gene encodes the only known protein inhibitor of zinc-dependent metallocarboxypeptidases. The encoded protein, latexin, downregulates the population size of hematopoietic stem cells. This protein is found to be downregulated in cancer cells because of promoter hypermethylation. [provided by RefSeq, Jul 2020]

GFM1 (HGNC:13780): (G elongation factor mitochondrial 1) Eukaryotes contain two protein translational systems, one in the cytoplasm and one in the mitochondria. Mitochondrial translation is crucial for maintaining mitochondrial function and mutations in this system lead to a breakdown in the respiratory chain-oxidative phosphorylation system and to impaired maintenance of mitochondrial DNA. This gene encodes one of the mitochondrial translation elongation factors. Its role in the regulation of normal mitochondrial function and in different disease states attributed to mitochondrial dysfunction is not known. [provided by RefSeq, Jul 2008]

GFM1 Gene-Disease associations (from GenCC):

• hepatoencephalopathy due to combined oxidative phosphorylation defect type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=2.5842259E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LXN	NM_020169.4	c.158A>G	p.His53Arg	missense_variant	Exon 2 of 6	ENST00000264265.4	NP_064554.3
GFM1	NM_024996.7	c.1601+4605T>C		intron_variant	Intron 13 of 17	ENST00000486715.6	NP_079272.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LXN	ENST00000264265.4	c.158A>G	p.His53Arg	missense_variant	Exon 2 of 6	1	NM_020169.4	ENSP00000264265.3
GFM1	ENST00000486715.6	c.1601+4605T>C		intron_variant	Intron 13 of 17	1	NM_024996.7	ENSP00000419038.1

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87268 AN: 151944 Hom.: 25803 Cov.: 33

Gnomad AFR AF: 0.713

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.555

GnomAD2 exomes AF: 0.513 AC: 99591 AN: 194202 AF XY: 0.515

Gnomad AFR exome AF: 0.689

Gnomad AMR exome AF: 0.518

Gnomad ASJ exome AF: 0.480

Gnomad EAS exome AF: 0.295

Gnomad FIN exome AF: 0.508

Gnomad NFE exome AF: 0.512

Gnomad OTH exome AF: 0.486

GnomAD4 exome AF: 0.525 AC: 719019 AN: 1370818 Hom.: 191372 Cov.: 37 AF XY: 0.525 AC XY: 356762 AN XY: 679122

African (AFR) AF: 0.710 AC: 20036 AN: 28228

American (AMR) AF: 0.518 AC: 14991 AN: 28950

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 11537 AN: 23132

East Asian (EAS) AF: 0.340 AC: 12190 AN: 35846

South Asian (SAS) AF: 0.591 AC: 44232 AN: 74784

European-Finnish (FIN) AF: 0.500 AC: 24824 AN: 49674

Middle Eastern (MID) AF: 0.550 AC: 2978 AN: 5410

European-Non Finnish (NFE) AF: 0.523 AC: 558691 AN: 1068774

Other (OTH) AF: 0.527 AC: 29540 AN: 56020

GnomAD4 genome AF: 0.574 AC: 87357 AN: 152062 Hom.: 25840 Cov.: 33 AF XY: 0.575 AC XY: 42755 AN XY: 74346

African (AFR) AF: 0.713 AC: 29590 AN: 41480

American (AMR) AF: 0.536 AC: 8199 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1762 AN: 3472

East Asian (EAS) AF: 0.339 AC: 1753 AN: 5176

South Asian (SAS) AF: 0.599 AC: 2884 AN: 4814

European-Finnish (FIN) AF: 0.529 AC: 5584 AN: 10548

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35791 AN: 67972

Other (OTH) AF: 0.560 AC: 1182 AN: 2110

Alfa AF: 0.544 Hom.: 61905

Bravo AF: 0.580

TwinsUK AF: 0.524 AC: 1942

ALSPAC AF: 0.529 AC: 2040

ESP6500AA AF: 0.702 AC: 3060

ESP6500EA AF: 0.538 AC: 4622

ExAC AF: 0.543 AC: 65842

Asia WGS AF: 0.544 AC: 1891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.2
DANN	Benign	0.85
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.000026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.67	N
PhyloP100		0.15
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.048
Sift	Benign	0.42	T
Sift4G	Benign	0.43	T
Polyphen		0.0010	B
Vest4		0.016
MPC		0.31
ClinPred		0.0050	T
GERP RS		-2.5
Varity_R		0.064
gMVP		0.37
Mutation Taster		=88/12	polymorphism (auto)

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: rs8455; hg19: chr3-158388780; COSMIC: COSV51834864; COSMIC: COSV51834864;