NM_003413.4:c.162T>C

Variant names:

• chrX-137566853-T-C
• rs62637689
• NM_003413.4:c.162T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003413.4(ZIC3):​c.162T>C​(p.Ala54Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,160,326 control chromosomes in the GnomAD database, including 15 homozygotes. There are 634 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (7 hom., 313 hem., cov: 25)
  • Exomes 𝑓: 0.0012 (8 hom. 321 hem.)
• Consequence: ZIC3 NM_003413.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.87
• Publications: 2 publications found

Genes affected

ZIC3 (HGNC:12874): (Zic family member 3) This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. This nuclear protein probably functions as a transcription factor in early stages of left-right body axis formation. Mutations in this gene cause X-linked visceral heterotaxy, which includes congenital heart disease and left-right axis defects in organs. [provided by RefSeq, Jul 2008]

LINC02931 (HGNC:55853): (long intergenic non-protein coding RNA 2931)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-137566853-T-C is Benign according to our data. Variant chrX-137566853-T-C is described in ClinVar as Benign. ClinVar VariationId is 137958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.87 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00919 (1037/112782) while in subpopulation AFR AF = 0.0302 (942/31201). AF 95% confidence interval is 0.0286. There are 7 homozygotes in GnomAd4. There are 313 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003413.4. 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
	ZIC3	NM_003413.4	MANE Select	c.162T>C	p.Ala54Ala	synonymous	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.162T>C	p.Ala54Ala	synonymous	Exon 1 of 3	NP_001317590.1	O60481-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC3	ENST00000287538.10	TSL:1 MANE Select	c.162T>C	p.Ala54Ala	synonymous	Exon 1 of 3	ENSP00000287538.5	O60481-1
	ZIC3	ENST00000919832.1		c.162T>C	p.Ala54Ala	synonymous	Exon 4 of 6	ENSP00000589891.1
	ZIC3	ENST00000919833.1		c.162T>C	p.Ala54Ala	synonymous	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes AF: 0.00917 AC: 1034 AN: 112728 Hom.: 7 Cov.: 25

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00480

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000848

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000394

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00229 AC: 235 AN: 102752 AF XY: 0.00152

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00201

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000417

Gnomad OTH exome AF: 0.00226

GnomAD4 exome AF: 0.00116 AC: 1211 AN: 1047544 Hom.: 8 Cov.: 33 AF XY: 0.000940 AC XY: 321 AN XY: 341514

African (AFR) AF: 0.0293 AC: 730 AN: 24884

American (AMR) AF: 0.00283 AC: 79 AN: 27932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18599

East Asian (EAS) AF: 0.000515 AC: 14 AN: 27170

South Asian (SAS) AF: 0.0000402 AC: 2 AN: 49762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32851

Middle Eastern (MID) AF: 0.00421 AC: 17 AN: 4036

European-Non Finnish (NFE) AF: 0.000268 AC: 219 AN: 818068

Other (OTH) AF: 0.00339 AC: 150 AN: 44242

GnomAD4 genome AF: 0.00919 AC: 1037 AN: 112782 Hom.: 7 Cov.: 25 AF XY: 0.00893 AC XY: 313 AN XY: 35054

African (AFR) AF: 0.0302 AC: 942 AN: 31201

American (AMR) AF: 0.00479 AC: 52 AN: 10855

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.000851 AC: 3 AN: 3526

South Asian (SAS) AF: 0.00 AC: 0 AN: 2750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6077

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000394 AC: 21 AN: 53260

Other (OTH) AF: 0.0122 AC: 19 AN: 1552

Alfa AF: 0.00465 Hom.: 26

Bravo AF: 0.0107

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Heterotaxy, visceral, 1, X-linked (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.60
PhyloP100		-2.9
PromoterAI		0.0056	Neutral
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: rs62637689; hg19: chrX-136649012;