rs35942089

Variant names:

• chr3-158645674-A-G
• rs35942089
• NM_024996.7:c.127A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-158645674-A-G
• chr3-158645674-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374357.1(GFM1):​c.-99A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,611,068 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (16 hom., cov: 33)
  • Exomes 𝑓: 0.011 (119 hom.)
• Consequence: GFM1 NM_001374357.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 8.87
• Publications: 6 publications found

Genes affected

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]

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008831739).
• BP6: Variant 3-158645674-A-G is Benign according to our data. Variant chr3-158645674-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00889 (1354/152320) while in subpopulation NFE AF = 0.014 (953/68030). AF 95% confidence interval is 0.0133. There are 16 homozygotes in GnomAd4. There are 647 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374357.1. 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
	GFM1	NM_024996.7	MANE Select	c.127A>G	p.Asn43Asp	missense	Exon 2 of 18	NP_079272.4
	GFM1	NM_001374357.1		c.-99A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	NP_001361286.1
	GFM1	NM_001374359.1		c.-103A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 16	NP_001361288.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFM1	ENST00000486715.6	TSL:1 MANE Select	c.127A>G	p.Asn43Asp	missense	Exon 2 of 18	ENSP00000419038.1	Q96RP9-1
	GFM1	ENST00000464732.1	TSL:3	c.-99A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000417532.1	C9JA25
	GFM1	ENST00000867690.1		c.127A>G	p.Asn43Asp	missense	Exon 2 of 19	ENSP00000537749.1

Frequencies

GnomAD3 genomes AF: 0.00890 AC: 1354 AN: 152202 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.0237

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.00933

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00961 AC: 2416 AN: 251432 AF XY: 0.00990

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.0204

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.0112 AC: 16352 AN: 1458748 Hom.: 119 Cov.: 30 AF XY: 0.0115 AC XY: 8325 AN XY: 725894

African (AFR) AF: 0.00150 AC: 50 AN: 33430

American (AMR) AF: 0.00369 AC: 165 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 505 AN: 26106

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39672

South Asian (SAS) AF: 0.00762 AC: 657 AN: 86190

European-Finnish (FIN) AF: 0.0126 AC: 674 AN: 53412

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5764

European-Non Finnish (NFE) AF: 0.0123 AC: 13675 AN: 1109170

Other (OTH) AF: 0.0101 AC: 610 AN: 60288

GnomAD4 genome AF: 0.00889 AC: 1354 AN: 152320 Hom.: 16 Cov.: 33 AF XY: 0.00869 AC XY: 647 AN XY: 74466

African (AFR) AF: 0.00180 AC: 75 AN: 41576

American (AMR) AF: 0.00451 AC: 69 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 82 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00870 AC: 42 AN: 4826

European-Finnish (FIN) AF: 0.00933 AC: 99 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0140 AC: 953 AN: 68030

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.0125 Hom.: 53

Bravo AF: 0.00732

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0145 AC: 125

ExAC AF: 0.00982 AC: 1192

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0122

EpiControl AF: 0.0100

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (4)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.0059
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.23
Sift	Benign	0.65	T
Sift4G	Benign	0.33	T
Polyphen		0.0040	B
Vest4		0.68
MVP		0.61
MPC		0.28
ClinPred		0.056	T
GERP RS		5.4
Varity_R		0.34
gMVP		0.91
Mutation Taster		=99/1	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: rs35942089; hg19: chr3-158363463; COSMIC: COSV108045339; COSMIC: COSV108045339;