chr3-147391095-C-A

Variant names:

• chr3-147391095-C-A
• rs75921971
• NM_032153.6:c.840G>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_032153.6(ZIC4):​c.840G>T​(p.Ser280Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000776 in 1,614,138 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (6 hom.)
• Consequence: ZIC4 NM_032153.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0280
• Publications: 0 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 3-147391095-C-A is Benign according to our data. Variant chr3-147391095-C-A is described in ClinVar as Benign. ClinVar VariationId is 729089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.028 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 8 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.840G>T	p.Ser280Ser	synonymous	Exon 4 of 5	NP_115529.2
	ZIC4	NM_001168378.1		c.990G>T	p.Ser330Ser	synonymous	Exon 4 of 5	NP_001161850.1	Q8N9L1-3
	ZIC4	NM_001168379.2		c.954G>T	p.Ser318Ser	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.840G>T	p.Ser280Ser	synonymous	Exon 4 of 5	ENSP00000372553.3	Q8N9L1-1
	ZIC4	ENST00000525172.6	TSL:2	c.990G>T	p.Ser330Ser	synonymous	Exon 4 of 5	ENSP00000435509.2	Q8N9L1-3
	ZIC4	ENST00000425731.7	TSL:2	c.954G>T	p.Ser318Ser	synonymous	Exon 4 of 5	ENSP00000397695.3	Q8N9L1-5

Frequencies

GnomAD3 genomes AF: 0.00424 AC: 646 AN: 152250 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000938 AC: 234 AN: 249362 AF XY: 0.000658

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.000290

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: 0.000494

GnomAD4 exome AF: 0.000415 AC: 606 AN: 1461770 Hom.: 6 Cov.: 31 AF XY: 0.000322 AC XY: 234 AN XY: 727188

African (AFR) AF: 0.0151 AC: 504 AN: 33480

American (AMR) AF: 0.000649 AC: 29 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

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

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112002

Other (OTH) AF: 0.000977 AC: 59 AN: 60396

GnomAD4 genome AF: 0.00424 AC: 646 AN: 152368 Hom.: 8 Cov.: 33 AF XY: 0.00405 AC XY: 302 AN XY: 74498

African (AFR) AF: 0.0144 AC: 598 AN: 41598

American (AMR) AF: 0.00287 AC: 44 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68042

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00261 Hom.: 1

Bravo AF: 0.00468

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	7.7
DANN	Benign	0.94
PhyloP100		-0.028

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs75921971; hg19: chr3-147108882;