chr17-57979243-T-TTGTTGCTGC

Variant names:

• chr17-57979243-T-TTGTTGCTGC
• rs914850486
• NM_007146.3:c.1046_1047insGCAGCAACA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_007146.3(VEZF1):​c.1046_1047insGCAGCAACA​(p.Gln347_Gln349dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000958 in 1,596,570 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q349Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00097 (1 hom.)
• Consequence: VEZF1 NM_007146.3 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.405
• Publications: 0 publications found

Genes affected

VEZF1 (HGNC:12949): (vascular endothelial zinc finger 1) Transcriptional regulatory proteins containing tandemly repeated zinc finger domains are thought to be involved in both normal and abnormal cellular proliferation and differentiation. ZNF161 is a C2H2-type zinc finger protein (Koyano-Nakagawa et al., 1994 [PubMed 8035792]). See MIM 603971 for general information on zinc finger proteins.[supplied by OMIM, Sep 2008]

VEZF1 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• cardiomyopathy, dilated, 100

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_007146.3
• BS2: High AC in GnomAd4 at 122 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007146.3. 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
	VEZF1	NM_007146.3	MANE Select	c.1046_1047insGCAGCAACA	p.Gln347_Gln349dup	disruptive_inframe_insertion	Exon 5 of 6	NP_009077.2	Q14119
	VEZF1	NM_001330393.2		c.1019_1020insGCAGCAACA	p.Gln338_Gln340dup	disruptive_inframe_insertion	Exon 6 of 7	NP_001317322.1	J3QSH4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEZF1	ENST00000581208.2	TSL:1 MANE Select	c.1046_1047insGCAGCAACA	p.Gln347_Gln349dup	disruptive_inframe_insertion	Exon 5 of 6	ENSP00000462337.1	Q14119
	VEZF1	ENST00000258963.7	TSL:1	c.500_501insGCAGCAACA	p.Gln165_Gln167dup	disruptive_inframe_insertion	Exon 4 of 5	ENSP00000258963.3	J9JIC7
	VEZF1	ENST00000905172.1		c.1187_1188insGCAGCAACA	p.Gln394_Gln396dup	disruptive_inframe_insertion	Exon 6 of 7	ENSP00000575231.1

Frequencies

GnomAD3 genomes AF: 0.000810 AC: 122 AN: 150644 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00126

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: 0.00137

Gnomad OTH AF: 0.00242

GnomAD4 exome AF: 0.000973 AC: 1407 AN: 1445814 Hom.: 1 Cov.: 32 AF XY: 0.000926 AC XY: 666 AN XY: 719298

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

African (AFR) AF: 0.0000911 AC: 3 AN: 32928

American (AMR) AF: 0.000384 AC: 17 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25812

East Asian (EAS) AF: 0.00 AC: 0 AN: 39308

South Asian (SAS) AF: 0.000248 AC: 21 AN: 84796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52620

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5636

European-Non Finnish (NFE) AF: 0.00120 AC: 1319 AN: 1100732

Other (OTH) AF: 0.000771 AC: 46 AN: 59656

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000809 AC: 122 AN: 150756 Hom.: 0 Cov.: 28 AF XY: 0.000814 AC XY: 60 AN XY: 73668

African (AFR) AF: 0.000122 AC: 5 AN: 40900

American (AMR) AF: 0.00125 AC: 19 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00138 AC: 93 AN: 67634

Other (OTH) AF: 0.00240 AC: 5 AN: 2086

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.41
Mutation Taster		=80/20	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs914850486; hg19: chr17-56056604;