Genetic Variant NM_001698.3:c.182C>A (chr9-91361708-G-T) – 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_001698.3(AUH):c.182C>A(p.Pro61His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000873 in 1,555,180 control chromosomes in the GnomAD database, including 12 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 7 hom. )

Consequence

AUH
NM_001698.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.143

Publications

0 publications found

Variant links:

Genes affected

AUH (HGNC:890): (AU RNA binding methylglutaconyl-CoA hydratase) This gene encodes bifunctional mitochondrial protein that has both RNA-binding and hydratase activities. The encoded protein is a methylglutaconyl-CoA hydratase that catalyzes the hydration of 3-methylglutaconyl-CoA to 3-hydroxy-3-methyl-glutaryl-CoA, a critical step in the leucine degradation pathway. This protein also binds AU-rich elements (AREs) found in the 3' UTRs of rapidly decaying mRNAs including c-fos, c-myc and granulocyte/ macrophage colony stimulating factor. ARE elements are involved in directing RNA to rapid degradation and deadenylation. This protein is localizes to the mitochondrial matrix and the inner mitochondrial membrane and may be involved in mitochondrial protein synthesis. Mutations in this gene are the cause of 3-methylglutaconic aciduria, type I. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

AUH Gene-Disease associations (from GenCC):

3-methylglutaconic aciduria type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

AUH 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=0.0039705336).

BP6

Variant 9-91361708-G-T is Benign according to our data. Variant chr9-91361708-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 214144.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 = 0.00451 (687/152268) while in subpopulation AFR AF = 0.0159 (659/41560). AF 95% confidence interval is 0.0149. There are 5 homozygotes in GnomAd4. There are 325 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001698.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AUH	NM_001698.3	MANE Select	c.182C>A	p.Pro61His	missense	Exon 1 of 10	NP_001689.1	Q13825-1
AUH	NM_001306190.2		c.182C>A	p.Pro61His	missense	Exon 1 of 9	NP_001293119.1	Q13825-2
AUH	NM_001351431.2		c.-216C>A		5_prime_UTR	Exon 1 of 11	NP_001338360.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AUH	ENST00000375731.9	TSL:1 MANE Select	c.182C>A	p.Pro61His	missense	Exon 1 of 10	ENSP00000364883.5	Q13825-1
AUH	ENST00000303617.5	TSL:1	c.182C>A	p.Pro61His	missense	Exon 1 of 9	ENSP00000307334.5	Q13825-2
AUH	ENST00000895926.1		c.182C>A	p.Pro61His	missense	Exon 1 of 11	ENSP00000565985.1

Frequencies

GnomAD3 genomes

AF:

0.00451

AC:

686

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00115

AC:

177

AN:

153412

AF XY:

0.000800

show subpopulations

Gnomad AFR exome

AF:

0.0191

Gnomad AMR exome

AF:

0.000929

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000682

Gnomad OTH exome

AF:

0.000695

GnomAD4 exome

AF:

0.000478

AC:

670

AN:

1402912

Hom.:

Cov.:

AF XY:

0.000391

AC XY:

271

AN XY:

692570

show subpopulations

African (AFR)

AF:

0.0177

AC:

558

AN:

31608

American (AMR)

AF:

0.00108

AC:

AN:

36256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25064

East Asian (EAS)

AF:

0.00

AC:

AN:

36336

South Asian (SAS)

AF:

0.0000504

AC:

AN:

79422

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48538

Middle Eastern (MID)

AF:

0.000879

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00000924

AC:

AN:

1081858

Other (OTH)

AF:

0.000929

AC:

AN:

58142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00451

AC:

687

AN:

152268

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

325

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0159

AC:

659

AN:

41560

American (AMR)

AF:

0.000980

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68014

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

101

135

169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00134

Hom.:

Bravo

AF:

0.00513

ESP6500AA

AF:

0.0149

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.000946

AC:

105

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

3-methylglutaconic aciduria type 1 (2)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

-0.14

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.62

REVEL

Benign

0.021

Sift

Benign

0.17

Sift4G

Benign

0.21

Polyphen

0.16

Vest4

0.27

MVP

0.36

MPC

0.44

ClinPred

0.016

GERP RS

1.8

PromoterAI

0.059

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.088

gMVP

0.22

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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