chr3-12960431-G-A

Variant names:

• chr3-12960431-G-A
• rs765248
• NM_001134382.3:c.24-18566C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001134382.3(IQSEC1):​c.24-18566C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 152,026 control chromosomes in the GnomAD database, including 11,503 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (11500 hom., cov: 31)
  • Exomes 𝑓: 0.36 (3 hom.)
• Consequence: IQSEC1 NM_001134382.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.287
• Publications: 2 publications found

Genes affected

IQSEC1 (HGNC:29112): (IQ motif and Sec7 domain ArfGEF 1) Predicted to enable protein kinase binding activity. Predicted to be involved in several processes, including positive regulation of focal adhesion disassembly; positive regulation of keratinocyte migration; and regulation of postsynaptic neurotransmitter receptor internalization. Located in nucleolus. Implicated in intellectual developmental disorder with short stature and behavioral abnormalities. [provided by Alliance of Genome Resources, Apr 2022]

IQSEC1 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with short stature and behavioral abnormalities

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134382.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC1	NM_001134382.3	MANE Select	c.24-18566C>T		intron	N/A	NP_001127854.1
	IQSEC1	NM_001376938.2		c.348-18566C>T		intron	N/A	NP_001363867.1
	IQSEC1	NM_014869.8		c.65+6956C>T		intron	N/A	NP_055684.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC1	ENST00000613206.2	TSL:2 MANE Select	c.24-18566C>T		intron	N/A	ENSP00000480301.1
	IQSEC1	ENST00000273221.8	TSL:1	c.65+6956C>T		intron	N/A	ENSP00000273221.4
	IQSEC1	ENST00000618604.4	TSL:1	c.-301-18566C>T		intron	N/A	ENSP00000478001.1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56495 AN: 151866 Hom.: 11504 Cov.: 31

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.432

GnomAD4 exome AF: 0.357 AC: 15 AN: 42 Hom.: 3 Cov.: 0 AF XY: 0.441 AC XY: 15 AN XY: 34

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.167 AC: 1 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.433 AC: 13 AN: 30

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.372 AC: 56499 AN: 151984 Hom.: 11500 Cov.: 31 AF XY: 0.364 AC XY: 27074 AN XY: 74282

African (AFR) AF: 0.239 AC: 9913 AN: 41438

American (AMR) AF: 0.427 AC: 6530 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1646 AN: 3464

East Asian (EAS) AF: 0.105 AC: 544 AN: 5176

South Asian (SAS) AF: 0.194 AC: 937 AN: 4818

European-Finnish (FIN) AF: 0.403 AC: 4255 AN: 10556

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.458 AC: 31094 AN: 67932

Other (OTH) AF: 0.429 AC: 906 AN: 2110

Alfa AF: 0.437 Hom.: 20959

Bravo AF: 0.374

Asia WGS AF: 0.209 AC: 731 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	13
DANN	Benign	0.55
PhyloP100		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs765248; hg19: chr3-13001931;