15-67279399-C-T

Variant names:

• chr15-67279399-C-T
• rs1966257020
• NM_001031715.3:c.274C>T

Variant summary

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

The NM_001031715.3(IQCH):​c.274C>T​(p.Leu92Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IQCH NM_001031715.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.144

Genes affected

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

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=0.03523156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQCH	NM_001031715.3	c.274C>T	p.Leu92Phe	missense_variant	Exon 4 of 21	ENST00000335894.9	NP_001026885.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQCH	ENST00000335894.9	c.274C>T	p.Leu92Phe	missense_variant	Exon 4 of 21	1	NM_001031715.3	ENSP00000336861.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1408098 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 703062

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.274C>T (p.L92F) alteration is located in exon 4 (coding exon 4) of the IQCH gene. This alteration results from a C to T substitution at nucleotide position 274, causing the leucine (L) at amino acid position 92 to be replaced by a phenylalanine (F). 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	0.088
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	.;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.035	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.23	N;N
REVEL	Benign	0.068
Sift	Benign	0.21	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0040	.;B
Vest4		0.16
MutPred		0.29		Loss of stability (P = 0.0682);Loss of stability (P = 0.0682);
MVP		0.18
MPC		0.11
ClinPred		0.054	T
GERP RS		-0.25
Varity_R		0.039
gMVP		0.085

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs1966257020; hg19: chr15-67571737;