15-67261345-A-G

Position:

• chr15-67261345-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001031715.3(IQCH):​c.125A>G​(p.Asp42Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,441,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IQCH NM_001031715.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32724684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQCH	NM_001031715.3	c.125A>G	p.Asp42Gly	missense_variant	2/21	ENST00000335894.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQCH	ENST00000335894.9	c.125A>G	p.Asp42Gly	missense_variant	2/21	1	NM_001031715.3	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441132 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 717056

Gnomad4 AFR exome AF: 0.0000313

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: 9.04e-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

Jan 06, 2023

The c.125A>G (p.D42G) alteration is located in exon 2 (coding exon 2) of the IQCH gene. This alteration results from a A to G substitution at nucleotide position 125, causing the aspartic acid (D) at amino acid position 42 to be replaced by a glycine (G). 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	0.30
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.63	D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.041	D;T
Polyphen		0.054	.;B
Vest4		0.65
MutPred		0.37		Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.27
MPC		0.31
ClinPred		0.83	D
GERP RS		5.7
Varity_R		0.28
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1232642249; hg19: chr15-67553683;