chr1-10949622-G-A

Variant names:

• chr1-10949622-G-A
• rs1281013
• NM_001170754.2:c.1290+2C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The NM_001170754.2(CIROZ):​c.1290+2C>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.043 in 1,598,944 control chromosomes in the GnomAD database, including 2,466 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.077 (791 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1675 hom.)
• Consequence: CIROZ NM_001170754.2 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115
• Publications: 12 publications found

Genes affected

CIROZ (HGNC:26730): (chromosome 1 open reading frame 127) Predicted to be involved in heart development. Predicted to act upstream of or within determination of left/right symmetry. [provided by Alliance of Genome Resources, Apr 2022]

CIROZ Gene-Disease associations (from GenCC):

• visceral heterotaxy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.077265374 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8, offset of 0 (no position change), new splice context is: aaaGTacgt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170754.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIROZ	NM_001170754.2	MANE Select	c.1290+2C>T		splice_donor intron	N/A	NP_001164225.1
	CIROZ	NM_001366227.2		c.873+2C>T		splice_donor intron	N/A	NP_001353156.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1orf127	ENST00000377004.9	TSL:5 MANE Select	c.1290+2C>T		splice_donor intron	N/A	ENSP00000366203.4
	C1orf127	ENST00000476357.1	TSL:2	n.130C>T		non_coding_transcript_exon	Exon 1 of 2
	C1orf127	ENST00000520253.1	TSL:5	c.1143+80C>T		intron	N/A	ENSP00000429704.1

Frequencies

GnomAD3 genomes AF: 0.0770 AC: 11706 AN: 152112 Hom.: 789 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0319

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.00423

Gnomad SAS AF: 0.0290

Gnomad FIN AF: 0.0571

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.0381

Gnomad OTH AF: 0.0589

GnomAD2 exomes AF: 0.0391 AC: 8784 AN: 224452 AF XY: 0.0365

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.0188

Gnomad ASJ exome AF: 0.0443

Gnomad EAS exome AF: 0.00454

Gnomad FIN exome AF: 0.0505

Gnomad NFE exome AF: 0.0338

Gnomad OTH exome AF: 0.0386

GnomAD4 exome AF: 0.0394 AC: 56948 AN: 1446714 Hom.: 1675 Cov.: 31 AF XY: 0.0385 AC XY: 27654 AN XY: 718242

African (AFR) AF: 0.198 AC: 6550 AN: 33124

American (AMR) AF: 0.0210 AC: 901 AN: 42954

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 1106 AN: 25784

East Asian (EAS) AF: 0.00319 AC: 125 AN: 39188

South Asian (SAS) AF: 0.0307 AC: 2556 AN: 83340

European-Finnish (FIN) AF: 0.0532 AC: 2786 AN: 52380

Middle Eastern (MID) AF: 0.0561 AC: 274 AN: 4880

European-Non Finnish (NFE) AF: 0.0363 AC: 40111 AN: 1105306

Other (OTH) AF: 0.0425 AC: 2539 AN: 59758

GnomAD4 genome AF: 0.0771 AC: 11734 AN: 152230 Hom.: 791 Cov.: 32 AF XY: 0.0750 AC XY: 5579 AN XY: 74430

African (AFR) AF: 0.182 AC: 7543 AN: 41500

American (AMR) AF: 0.0318 AC: 486 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3470

East Asian (EAS) AF: 0.00424 AC: 22 AN: 5188

South Asian (SAS) AF: 0.0290 AC: 140 AN: 4824

European-Finnish (FIN) AF: 0.0571 AC: 606 AN: 10616

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.0381 AC: 2592 AN: 68018

Other (OTH) AF: 0.0583 AC: 123 AN: 2110

Alfa AF: 0.0483 Hom.: 1294

Bravo AF: 0.0800

TwinsUK AF: 0.0329 AC: 122

ALSPAC AF: 0.0381 AC: 147

ESP6500AA AF: 0.163 AC: 719

ESP6500EA AF: 0.0385 AC: 331

ExAC AF: 0.0395 AC: 4790

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.5
DANN	Benign	0.40
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.023	N
PhyloP100		0.12
GERP RS		-0.58
Mutation Taster		=97/3	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: rs1281013; hg19: chr1-11009679; COSMIC: COSV65437216; COSMIC: COSV65437216;