15-67254920-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001031715.3(IQCH):c.24C>G(p.His8Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IQCH NM_001031715.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.617

Genes affected

IQCH (HGNC:25721): (IQ motif containing H)

AAGAB (HGNC:25662): (alpha and gamma adaptin binding protein) The protein encoded by this gene interacts with the gamma-adaptin and alpha-adaptin subunits of complexes involved in clathrin-coated vesicle trafficking. Mutations in this gene are associated with type I punctate palmoplantar keratoderma. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024815619).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQCH	NM_001031715.3	c.24C>G	p.His8Gln	missense_variant	1/21	ENST00000335894.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQCH	ENST00000335894.9	c.24C>G	p.His8Gln	missense_variant	1/21	1	NM_001031715.3	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461478 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.24C>G (p.H8Q) alteration is located in exon 1 (coding exon 1) of the IQCH gene. This alteration results from a C to G substitution at nucleotide position 24, causing the histidine (H) at amino acid position 8 to be replaced by a glutamine (Q). 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	Benign	0.083
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.82
Dann	Benign	0.69
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.025	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	D;D;D;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.070	N;N
REVEL	Benign	0.043
Sift	Benign	0.38	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.0010	.;B
Vest4		0.15
MutPred		0.11		Gain of solvent accessibility (P = 0.0338);Gain of solvent accessibility (P = 0.0338);
MVP		0.014
MPC		0.10
ClinPred		0.090	T
GERP RS		-2.0
Varity_R		0.063
gMVP		0.042

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-67547258;