rs62288347

Variant names:

• chr3-158690243-G-A
• rs62288347
• NM_024996.7:c.1990G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-158690243-G-A
• chr3-158690243-G-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_024996.7(GFM1):​c.1990G>A​(p.Val664Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,613,648 control chromosomes in the GnomAD database, including 331 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (26 hom., cov: 33)
  • Exomes 𝑓: 0.018 (305 hom.)
• Consequence: GFM1 NM_024996.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.64
• Publications: 10 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]

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), G2P, Orphanet
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044956803).
• BP6: Variant 3-158690243-G-A is Benign according to our data. Variant chr3-158690243-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137466.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 = 0.0146 (2220/152114) while in subpopulation NFE AF = 0.0186 (1267/68006). AF 95% confidence interval is 0.0178. There are 26 homozygotes in GnomAd4. There are 1190 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024996.7. 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.1990G>A	p.Val664Ile	missense	Exon 16 of 18	NP_079272.4
	GFM1	NM_001308164.2		c.2047G>A	p.Val683Ile	missense	Exon 17 of 19	NP_001295093.1	Q96RP9-2
	GFM1	NM_001374355.1		c.1909G>A	p.Val637Ile	missense	Exon 16 of 18	NP_001361284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFM1	ENST00000486715.6	TSL:1 MANE Select	c.1990G>A	p.Val664Ile	missense	Exon 16 of 18	ENSP00000419038.1	Q96RP9-1
	GFM1	ENST00000867690.1		c.2068G>A	p.Val690Ile	missense	Exon 17 of 19	ENSP00000537749.1
	GFM1	ENST00000867689.1		c.2062G>A	p.Val688Ile	missense	Exon 17 of 19	ENSP00000537748.1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2220 AN: 151996 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00685

Gnomad FIN AF: 0.0591

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0168 AC: 4231 AN: 251444 AF XY: 0.0172

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.00705

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0586

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.0178 AC: 25963 AN: 1461534 Hom.: 305 Cov.: 32 AF XY: 0.0177 AC XY: 12897 AN XY: 727104

African (AFR) AF: 0.00272 AC: 91 AN: 33474

American (AMR) AF: 0.00452 AC: 202 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00731 AC: 191 AN: 26128

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39684

South Asian (SAS) AF: 0.00821 AC: 708 AN: 86256

European-Finnish (FIN) AF: 0.0557 AC: 2976 AN: 53416

Middle Eastern (MID) AF: 0.00625 AC: 36 AN: 5764

European-Non Finnish (NFE) AF: 0.0188 AC: 20848 AN: 1111706

Other (OTH) AF: 0.0150 AC: 905 AN: 60382

GnomAD4 genome AF: 0.0146 AC: 2220 AN: 152114 Hom.: 26 Cov.: 33 AF XY: 0.0160 AC XY: 1190 AN XY: 74354

African (AFR) AF: 0.00280 AC: 116 AN: 41502

American (AMR) AF: 0.00746 AC: 114 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4816

European-Finnish (FIN) AF: 0.0591 AC: 623 AN: 10548

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

European-Non Finnish (NFE) AF: 0.0186 AC: 1267 AN: 68006

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.0152 Hom.: 33

Bravo AF: 0.0106

TwinsUK AF: 0.0186 AC: 69

ALSPAC AF: 0.0171 AC: 66

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0203 AC: 175

ExAC AF: 0.0177 AC: 2148

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (3)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.18
Sift	Benign	0.33	T
Sift4G	Benign	0.31	T
Polyphen		0.76	P
Vest4		0.23
MPC		0.29
ClinPred		0.025	T
GERP RS		5.8
Varity_R		0.13
gMVP		0.67
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs62288347; hg19: chr3-158408032;