chr2-9488294-C-T

Variant names:

• chr2-9488294-C-T
• rs773465936
• NM_001039613.3:c.712C>T

Variant summary

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

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.77
• Publications: 0 publications found

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]

ADAM17 Gene-Disease associations (from GenCC):

• inflammatory skin and bowel disease, neonatal, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• neonatal inflammatory skin and bowel disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IAH1	NM_001039613.3	MANE Select	c.712C>T	p.Pro238Ser	missense	Exon 6 of 6	NP_001034702.1	Q2TAA2-1
	IAH1	NM_001320858.2		c.637C>T	p.Pro213Ser	missense	Exon 6 of 6	NP_001307787.1
	IAH1	NM_001320859.2		c.373C>T	p.Pro125Ser	missense	Exon 5 of 5	NP_001307788.1	Q2TAA2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IAH1	ENST00000497473.6	TSL:1 MANE Select	c.712C>T	p.Pro238Ser	missense	Exon 6 of 6	ENSP00000417580.1	Q2TAA2-1
	IAH1	ENST00000470914.5	TSL:1	c.373C>T	p.Pro125Ser	missense	Exon 5 of 5	ENSP00000419224.1	Q2TAA2-2
	IAH1	ENST00000492223.5	TSL:1	n.*504C>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000419368.1	F8WF34

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000203 AC: 5 AN: 246340 AF XY: 0.0000374

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33316

American (AMR) AF: 0.0000228 AC: 1 AN: 43826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5756

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111296

Other (OTH) AF: 0.0000166 AC: 1 AN: 60264

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.8
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	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
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs773465936; hg19: chr2-9628423;