3-147390969-C-G

Variant names:

• chr3-147390969-C-G
• rs17509456
• NM_032153.6:c.966G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_032153.6(ZIC4):​c.966G>C​(p.Ser322Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,612,086 control chromosomes in the GnomAD database, including 1,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S322S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.030 (108 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1281 hom.)
• Consequence: ZIC4 NM_032153.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.690
• Publications: 3 publications found

Genes affected

ZIC4 (HGNC:20393): (Zic family member 4) This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. Members of this family are important during development, and have been associated with X-linked visceral heterotaxy and holoprosencephaly type 5. This gene is closely linked to the gene encoding zinc finger protein of the cerebellum 1, a related family member on chromosome 3. Heterozygous deletion of these linked genes is involved in Dandy-Walker malformation, which is a congenital cerebellar malformation. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Dec 2009]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 3-147390969-C-G is Benign according to our data. Variant chr3-147390969-C-G is described in ClinVar as Benign. ClinVar VariationId is 130789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0295 (4496/152334) while in subpopulation NFE AF = 0.0478 (3251/68032). AF 95% confidence interval is 0.0464. There are 108 homozygotes in GnomAd4. There are 2091 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 108 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032153.6. 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
	ZIC4	NM_032153.6	MANE Select	c.966G>C	p.Ser322Ser	synonymous	Exon 4 of 5	NP_115529.2
	ZIC4	NM_001168378.1		c.1116G>C	p.Ser372Ser	synonymous	Exon 4 of 5	NP_001161850.1	Q8N9L1-3
	ZIC4	NM_001168379.2		c.1080G>C	p.Ser360Ser	synonymous	Exon 4 of 5	NP_001161851.1	Q8N9L1-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC4	ENST00000383075.8	TSL:1 MANE Select	c.966G>C	p.Ser322Ser	synonymous	Exon 4 of 5	ENSP00000372553.3	Q8N9L1-1
	ZIC4	ENST00000525172.6	TSL:2	c.1116G>C	p.Ser372Ser	synonymous	Exon 4 of 5	ENSP00000435509.2	Q8N9L1-3
	ZIC4	ENST00000425731.7	TSL:2	c.1080G>C	p.Ser360Ser	synonymous	Exon 4 of 5	ENSP00000397695.3	Q8N9L1-5

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4499 AN: 152216 Hom.: 108 Cov.: 33

Gnomad AFR AF: 0.00839

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0298

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0373

GnomAD2 exomes AF: 0.0299 AC: 7231 AN: 241788 AF XY: 0.0309

Gnomad AFR exome AF: 0.00767

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0330

Gnomad EAS exome AF: 0.0000565

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.0482

Gnomad OTH exome AF: 0.0364

GnomAD4 exome AF: 0.0388 AC: 56595 AN: 1459752 Hom.: 1281 Cov.: 31 AF XY: 0.0383 AC XY: 27814 AN XY: 726086

African (AFR) AF: 0.00652 AC: 218 AN: 33452

American (AMR) AF: 0.0214 AC: 956 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 848 AN: 26054

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39674

South Asian (SAS) AF: 0.0118 AC: 1013 AN: 86140

European-Finnish (FIN) AF: 0.0180 AC: 948 AN: 52542

Middle Eastern (MID) AF: 0.0483 AC: 276 AN: 5716

European-Non Finnish (NFE) AF: 0.0451 AC: 50163 AN: 1111212

Other (OTH) AF: 0.0360 AC: 2169 AN: 60318

GnomAD4 genome AF: 0.0295 AC: 4496 AN: 152334 Hom.: 108 Cov.: 33 AF XY: 0.0281 AC XY: 2091 AN XY: 74486

African (AFR) AF: 0.00837 AC: 348 AN: 41582

American (AMR) AF: 0.0297 AC: 455 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5162

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4830

European-Finnish (FIN) AF: 0.0146 AC: 155 AN: 10630

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0478 AC: 3251 AN: 68032

Other (OTH) AF: 0.0369 AC: 78 AN: 2114

Alfa AF: 0.0257 Hom.: 19

Bravo AF: 0.0294

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.0476

EpiControl AF: 0.0507

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.9
DANN	Benign	0.83
PhyloP100		-0.69

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: rs17509456; hg19: chr3-147108756; COSMIC: COSV67172910; COSMIC: COSV67172910;