chrX-137566357-C-T

Variant names:

• chrX-137566357-C-T
• rs181414932
• NM_003413.4:c.-335C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003413.4(ZIC3):​c.-335C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 319,276 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 9 hem., cov: 25)
  • Exomes 𝑓: 0.00021 (0 hom. 9 hem.)
• Consequence: ZIC3 NM_003413.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.98
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BS2: High Hemizygotes in GnomAd4 at 9 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.-335C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_003413.4	MANE Select	c.-335C>T		5_prime_UTR	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.-335C>T		5_prime_UTR_premature_start_codon_gain	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.-335C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000287538.5	O60481-1
	ZIC3	ENST00000287538.10	TSL:1 MANE Select	c.-335C>T		5_prime_UTR	Exon 1 of 3	ENSP00000287538.5	O60481-1
	ZIC3	ENST00000919832.1		c.-170-165C>T		intron	N/A	ENSP00000589891.1

Frequencies

GnomAD3 genomes AF: 0.000231 AC: 26 AN: 112328 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000556

Gnomad ASJ AF: 0.000753

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000282

Gnomad OTH AF: 0.000659

GnomAD4 exome AF: 0.000208 AC: 43 AN: 206901 Hom.: 0 Cov.: 0 AF XY: 0.000174 AC XY: 9 AN XY: 51605

African (AFR) AF: 0.00 AC: 0 AN: 6790

American (AMR) AF: 0.000337 AC: 3 AN: 8889

Ashkenazi Jewish (ASJ) AF: 0.000464 AC: 3 AN: 6471

East Asian (EAS) AF: 0.00 AC: 0 AN: 14287

South Asian (SAS) AF: 0.00 AC: 0 AN: 14412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13395

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 908

European-Non Finnish (NFE) AF: 0.000241 AC: 31 AN: 128813

Other (OTH) AF: 0.000464 AC: 6 AN: 12936

GnomAD4 genome AF: 0.000231 AC: 26 AN: 112375 Hom.: 0 Cov.: 25 AF XY: 0.000260 AC XY: 9 AN XY: 34555

African (AFR) AF: 0.0000322 AC: 1 AN: 31037

American (AMR) AF: 0.000556 AC: 6 AN: 10795

Ashkenazi Jewish (ASJ) AF: 0.000753 AC: 2 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3499

South Asian (SAS) AF: 0.00 AC: 0 AN: 2702

European-Finnish (FIN) AF: 0.000163 AC: 1 AN: 6139

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000282 AC: 15 AN: 53115

Other (OTH) AF: 0.000650 AC: 1 AN: 1538

Alfa AF: 0.000270 Hom.: 2

Bravo AF: 0.000223

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Heterotaxy, visceral, 1, X-linked (1)
-	1	-	VACTERL association, X-linked, with or without hydrocephalus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.96
PhyloP100		2.0
PromoterAI		-0.090	Neutral
Mutation Taster		=299/1	polymorphism

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: rs181414932; hg19: chrX-136648516;