17-57979243-T-TTGTTGC

Variant names:

• chr17-57979243-T-TTGTTGC
• rs914850486
• NM_007146.3:c.1046_1047insGCAACA

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_007146.3(VEZF1):​c.1046_1047insGCAACA​(p.Gln348_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 0.000352 in 1,597,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. Q349Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: VEZF1 NM_007146.3 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_007146.3
• BP6: Variant 17-57979243-T-TTGTTGC is Benign according to our data. Variant chr17-57979243-T-TTGTTGC is described in ClinVar as Likely_benign. ClinVar VariationId is 3911282.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 77 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_1047insGCAACA	p.Gln348_Gln349dup	disruptive_inframe_insertion	Exon 5 of 6	NP_009077.2	Q14119
	VEZF1	NM_001330393.2		c.1019_1020insGCAACA	p.Gln339_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_1047insGCAACA	p.Gln348_Gln349dup	disruptive_inframe_insertion	Exon 5 of 6	ENSP00000462337.1	Q14119
	VEZF1	ENST00000258963.7	TSL:1	c.500_501insGCAACA	p.Gln166_Gln167dup	disruptive_inframe_insertion	Exon 4 of 5	ENSP00000258963.3	J9JIC7
	VEZF1	ENST00000905172.1		c.1187_1188insGCAACA	p.Gln395_Gln396dup	disruptive_inframe_insertion	Exon 6 of 7	ENSP00000575231.1

Frequencies

GnomAD3 genomes AF: 0.000511 AC: 77 AN: 150648 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000331

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000399

Gnomad OTH AF: 0.000969

GnomAD4 exome AF: 0.000335 AC: 485 AN: 1446290 Hom.: 0 Cov.: 32 AF XY: 0.000311 AC XY: 224 AN XY: 719510

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

African (AFR) AF: 0.00103 AC: 34 AN: 32926

American (AMR) AF: 0.000158 AC: 7 AN: 44326

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

East Asian (EAS) AF: 0.000712 AC: 28 AN: 39308

South Asian (SAS) AF: 0.000259 AC: 22 AN: 84800

European-Finnish (FIN) AF: 0.0000950 AC: 5 AN: 52620

Middle Eastern (MID) AF: 0.000532 AC: 3 AN: 5636

European-Non Finnish (NFE) AF: 0.000319 AC: 351 AN: 1101196

Other (OTH) AF: 0.000587 AC: 35 AN: 59666

⚠️ 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: 0.000511 AC: 77 AN: 150760 Hom.: 0 Cov.: 28 AF XY: 0.000529 AC XY: 39 AN XY: 73668

African (AFR) AF: 0.00100 AC: 41 AN: 40900

American (AMR) AF: 0.000330 AC: 5 AN: 15142

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

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.000210 AC: 1 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: 0.000399 AC: 27 AN: 67638

Other (OTH) AF: 0.000959 AC: 2 AN: 2086

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

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; COSMIC: COSV51967924; COSMIC: COSV51967924;