Genetic Variant NM_001031715.3:c.737G>A (chr15-67359869-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001031715.3(IQCH):c.737G>A(p.Gly246Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

IQCH
NM_001031715.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.50

Publications

0 publications found

Variant links:

Genes affected

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

IQCH links:

IQCH-AS1 (HGNC:44104): (IQCH antisense RNA 1)

IQCH-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031715.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQCH	NM_001031715.3	MANE Select	c.737G>A	p.Gly246Glu	missense	Exon 8 of 21	NP_001026885.2	Q86VS3-1
IQCH	NM_001322475.2		c.218G>A	p.Gly73Glu	missense	Exon 6 of 18	NP_001309404.2
IQCH	NM_001322470.2		c.218G>A	p.Gly73Glu	missense	Exon 5 of 16	NP_001309399.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQCH	ENST00000335894.9	TSL:1 MANE Select	c.737G>A	p.Gly246Glu	missense	Exon 8 of 21	ENSP00000336861.4	Q86VS3-1
IQCH	ENST00000629425.2	TSL:1	c.218G>A	p.Gly73Glu	missense	Exon 5 of 7	ENSP00000486970.1	Q86VS3-3
IQCH	ENST00000514049.5	TSL:2	n.*220G>A		non_coding_transcript_exon	Exon 5 of 17	ENSP00000421223.1	D6RGG0

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251450

AF XY:

0.0000147

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461030

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726884

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111238

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.019

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.75

M_CAP

Benign

0.017

MetaRNN

Benign

0.049

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

PhyloP100

1.5

PrimateAI

Benign

0.42

PROVEAN

Benign

0.74

REVEL

Benign

0.047

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.15

Vest4

0.28

MVP

0.048

MPC

0.36

ClinPred

0.40

GERP RS

3.9

Varity_R

0.045

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.21

Position offset: 16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over