dbSNP rs34297061: GFM1:p.Asn159Ser (chr3-158646851-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024996.7(GFM1):c.476A>G(p.Asn159Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0024 in 1,614,110 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 37 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 55 hom. )

Consequence

GFM1
NM_024996.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.87

Publications

6 publications found

Variant links:

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 links:

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]

LXN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.011184692).

BP6

Variant 3-158646851-A-G is Benign according to our data. Variant chr3-158646851-A-G is described in ClinVar as Benign. ClinVar VariationId is 137464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1865/152240) while in subpopulation AFR AF = 0.0431 (1791/41516). AF 95% confidence interval is 0.0415. There are 37 homozygotes in GnomAd4. There are 889 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 37 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFM1	NM_024996.7	MANE Select	c.476A>G	p.Asn159Ser	missense	Exon 4 of 18	NP_079272.4
GFM1	NM_001308164.2		c.476A>G	p.Asn159Ser	missense	Exon 4 of 19	NP_001295093.1	Q96RP9-2
GFM1	NM_001374355.1		c.476A>G	p.Asn159Ser	missense	Exon 4 of 18	NP_001361284.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFM1	ENST00000486715.6	TSL:1 MANE Select	c.476A>G	p.Asn159Ser	missense	Exon 4 of 18	ENSP00000419038.1	Q96RP9-1
GFM1	ENST00000867690.1		c.476A>G	p.Asn159Ser	missense	Exon 4 of 19	ENSP00000537749.1
GFM1	ENST00000867689.1		c.476A>G	p.Asn159Ser	missense	Exon 4 of 19	ENSP00000537748.1

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1863

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0432

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00334

AC:

841

AN:

251470

AF XY:

0.00234

show subpopulations

Gnomad AFR exome

AF:

0.0452

Gnomad AMR exome

AF:

0.00208

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00137

AC:

2010

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

871

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0468

AC:

1566

AN:

33478

American (AMR)

AF:

0.00244

AC:

109

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000105

AC:

117

AN:

1111996

Other (OTH)

AF:

0.00320

AC:

193

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

105

210

314

419

524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0123

AC:

1865

AN:

152240

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

889

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0431

AC:

1791

AN:

41516

American (AMR)

AF:

0.00320

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68010

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

174

260

347

434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00476

Hom.:

Bravo

AF:

0.0141

ESP6500AA

AF:

0.0436

AC:

192

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00411

AC:

499

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (4)

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.20

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.4

PhyloP100

4.9

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.18

Sift

Benign

0.052

Sift4G

Benign

0.32

Polyphen

0.0060

Vest4

0.18

MVP

0.59

MPC

0.18

ClinPred

0.035

GERP RS

3.5

Varity_R

0.15

gMVP

0.80

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over