7-2572233-C-T

Variant names:

• chr7-2572233-C-T
• rs11976972
• NM_152558.5:c.301C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152558.5(IQCE):​c.301C>T​(p.His101Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H101N) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: IQCE NM_152558.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.780
• Publications: 7 publications found

Genes affected

IQCE (HGNC:29171): (IQ motif containing E) Involved in limb morphogenesis. Predicted to be extrinsic component of membrane. Predicted to be part of plasma membrane protein complex. [provided by Alliance of Genome Resources, Apr 2022]

IQCE Gene-Disease associations (from GenCC):

• postaxial polydactyly type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• polydactyly, postaxial, type a7

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06770074).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152558.5. 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
	IQCE	NM_152558.5	MANE Select	c.301C>T	p.His101Tyr	missense	Exon 5 of 22	NP_689771.3
	IQCE	NM_001287499.2		c.301C>T	p.His101Tyr	missense	Exon 5 of 21	NP_001274428.1	A0A087WX45
	IQCE	NM_001287500.2		c.253C>T	p.His85Tyr	missense	Exon 4 of 20	NP_001274429.1	A0A087WX19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQCE	ENST00000402050.7	TSL:1 MANE Select	c.301C>T	p.His101Tyr	missense	Exon 5 of 22	ENSP00000385597.2	Q6IPM2-1
	IQCE	ENST00000623361.3	TSL:1	c.106C>T	p.His36Tyr	missense	Exon 3 of 20	ENSP00000485601.1	Q6IPM2-2
	IQCE	ENST00000325997.13	TSL:1	n.*78C>T		non_coding_transcript_exon	Exon 3 of 20	ENSP00000314011.10	X5D7Y5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249504 AF XY: 0.00000739

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: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461816 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111948

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74360

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 48

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.61
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.78
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.034
Sift	Benign	1.0	T
Sift4G	Benign	0.55	T
Polyphen		0.053	B
Vest4		0.30
MutPred		0.34		Gain of phosphorylation at H101 (P = 0.0699)
MVP		0.36
MPC		0.14
ClinPred		0.052	T
GERP RS		2.0
Varity_R		0.056
gMVP		0.12
Mutation Taster		=99/1	polymorphism

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: rs11976972; hg19: chr7-2611867;