Genetic Variant IAH1:p.Ala2Val (chr2-9474571-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001039613.3(IAH1):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000595 in 1,513,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

IAH1
NM_001039613.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.49

Publications

0 publications found

Variant links:

Genes affected

IAH1 (HGNC:27696): (isoamyl acetate hydrolyzing esterase 1 (putative)) Enables identical protein binding activity. Predicted to be involved in lipid catabolic process. [provided by Alliance of Genome Resources, Apr 2022]

IAH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039613.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IAH1	NM_001039613.3	MANE Select	c.5C>T	p.Ala2Val	missense	Exon 1 of 6	NP_001034702.1	Q2TAA2-1
IAH1	NM_001320859.2		c.-282C>T		5_prime_UTR	Exon 1 of 5	NP_001307788.1	Q2TAA2-2
IAH1	NM_001320860.2		c.-250C>T		5_prime_UTR	Exon 1 of 5	NP_001307789.1	Q2TAA2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IAH1	ENST00000497473.6	TSL:1 MANE Select	c.5C>T	p.Ala2Val	missense	Exon 1 of 6	ENSP00000417580.1	Q2TAA2-1
IAH1	ENST00000470914.5	TSL:1	c.-282C>T		5_prime_UTR	Exon 1 of 5	ENSP00000419224.1	Q2TAA2-2
IAH1	ENST00000492223.5	TSL:1	n.5C>T		non_coding_transcript_exon	Exon 1 of 5	ENSP00000419368.1	F8WF34

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151348

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000133

AC:

AN:

150706

AF XY:

0.0000233

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000133

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000145

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000587

AC:

AN:

1362514

Hom.:

Cov.:

AF XY:

0.00000887

AC XY:

AN XY:

676672

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27602

American (AMR)

AF:

0.00

AC:

AN:

32990

Ashkenazi Jewish (ASJ)

AF:

0.0000425

AC:

AN:

23552

East Asian (EAS)

AF:

0.00

AC:

AN:

31546

South Asian (SAS)

AF:

0.00

AC:

AN:

77106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4620

European-Non Finnish (NFE)

AF:

0.00000562

AC:

AN:

1067288

Other (OTH)

AF:

0.0000179

AC:

AN:

55860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151348

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73898

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40952

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67868

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000862

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

Eigen

Benign

0.041

Eigen_PC

Benign

0.044

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.52

M_CAP

Pathogenic

0.88

MetaRNN

Uncertain

0.67

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.8

PhyloP100

2.5

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.98

REVEL

Benign

0.12

Sift

Uncertain

0.015

Sift4G

Uncertain

0.030

Polyphen

0.65

Vest4

0.46

MutPred

0.34

Loss of helix (P = 0.0376)

MVP

0.57

MPC

0.43

ClinPred

0.73

GERP RS

3.9

PromoterAI

-0.35

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.11

gMVP

0.70

Mutation Taster

=90/10

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over