NM_001039613.3:c.712C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001039613.3(IAH1):​c.712C>T​(p.Pro238Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000617 in 1,459,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

IAH1
NM_001039613.3 missense

Scores

6
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.77
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]
ADAM17 (HGNC:195): (ADAM metallopeptidase domain 17) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biologic processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded preproprotein is proteolytically processed to generate the mature protease. The encoded protease functions in the ectodomain shedding of tumor necrosis factor-alpha, in which soluble tumor necrosis factor-alpha is released from the membrane-bound precursor. This protease also functions in the processing of numerous other substrates, including cell adhesion proteins, cytokine and growth factor receptors and epidermal growth factor (EGF) receptor ligands, and plays a prominent role in the activation of the Notch signaling pathway. Elevated expression of this gene has been observed in specific cell types derived from psoriasis, rheumatoid arthritis, multiple sclerosis and Crohn's disease patients, suggesting that the encoded protein may play a role in autoimmune disease. Additionally, this protease may play a role in viral infection through its cleavage of ACE2, the cellular receptor for SARS-CoV and SARS-CoV-2. [provided by RefSeq, Aug 2020]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IAH1NM_001039613.3 linkc.712C>T p.Pro238Ser missense_variant Exon 6 of 6 ENST00000497473.6 NP_001034702.1 Q2TAA2-1A0A140VJL6
ADAM17NM_003183.6 linkc.*1883G>A downstream_gene_variant ENST00000310823.8 NP_003174.3 P78536-1B2RNB2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IAH1ENST00000497473.6 linkc.712C>T p.Pro238Ser missense_variant Exon 6 of 6 1 NM_001039613.3 ENSP00000417580.1 Q2TAA2-1
ADAM17ENST00000310823.8 linkc.*1883G>A downstream_gene_variant 1 NM_003183.6 ENSP00000309968.3 P78536-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000203
AC:
5
AN:
246340
Hom.:
0
AF XY:
0.0000374
AC XY:
5
AN XY:
133834
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.000503
GnomAD4 exome
AF:
0.00000617
AC:
9
AN:
1459290
Hom.:
0
Cov.:
30
AF XY:
0.0000110
AC XY:
8
AN XY:
726098
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000228
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000313
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000248
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 15, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.712C>T (p.P238S) alteration is located in exon 6 (coding exon 6) of the IAH1 gene. This alteration results from a C to T substitution at nucleotide position 712, causing the proline (P) at amino acid position 238 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.14
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
.;T;.
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.80
.;T;T
M_CAP
Benign
0.017
T
MetaRNN
Uncertain
0.50
T;T;T
MetaSVM
Uncertain
-0.18
T
MutationAssessor
Uncertain
2.4
.;M;.
PrimateAI
Benign
0.42
T
PROVEAN
Pathogenic
-6.2
D;D;D
REVEL
Uncertain
0.44
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.014
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.64
MutPred
0.53
.;Gain of loop (P = 0.0435);.;
MVP
0.67
MPC
0.67
ClinPred
0.94
D
GERP RS
5.7
Varity_R
0.77
gMVP
0.71

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs773465936; hg19: chr2-9628423; API