chrX-137566709-C-T

Variant names:

• chrX-137566709-C-T
• rs1602742253
• NM_003413.4:c.18C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_003413.4(ZIC3):​c.18C>T​(p.Asp6Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,085,314 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: ZIC3 NM_003413.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.472
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant X-137566709-C-T is Benign according to our data. Variant chrX-137566709-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 755186.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.472 with no splicing effect.

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.18C>T	p.Asp6Asp	synonymous	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.18C>T	p.Asp6Asp	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.18C>T	p.Asp6Asp	synonymous	Exon 1 of 3	ENSP00000287538.5	O60481-1
	ZIC3	ENST00000919832.1		c.18C>T	p.Asp6Asp	synonymous	Exon 4 of 6	ENSP00000589891.1
	ZIC3	ENST00000919833.1		c.18C>T	p.Asp6Asp	synonymous	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1085314 Hom.: 0 Cov.: 32 AF XY: 0.00000282 AC XY: 1 AN XY: 354166

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

African (AFR) AF: 0.00 AC: 0 AN: 26218

American (AMR) AF: 0.00 AC: 0 AN: 34124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19143

East Asian (EAS) AF: 0.00 AC: 0 AN: 29760

South Asian (SAS) AF: 0.00 AC: 0 AN: 52152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37493

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4006

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 836805

Other (OTH) AF: 0.0000219 AC: 1 AN: 45613

⚠️ 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 Cov.: 25

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Heterotaxy, visceral, 1, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.94
PhyloP100		0.47
PromoterAI		-0.016	Neutral

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: rs1602742253; hg19: chrX-136648868; COSMIC: COSV54977415; COSMIC: COSV54977415;