chr6-42173588-A-G

Variant names:

• chr6-42173588-A-G
• rs6937603
• NM_001384910.1:c.-26A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384910.1(GUCA1A):​c.-26A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,592,506 control chromosomes in the GnomAD database, including 8,388 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (4430 hom., cov: 33)
  • Exomes 𝑓: 0.015 (3958 hom.)
• Consequence: GUCA1A NM_001384910.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.226

Genes affected

GUCA1A (HGNC:4678): (guanylate cyclase activator 1A) This gene encodes an enzyme that plays a role in the recovery of retinal photoreceptors from photobleaching. This enzyme promotes the activity of retinal guanylyl cyclase-1 (GC1) at low calcium concentrations and inhibits GC1 at high calcium concentrations. Mutations in this gene can cause cone dystrophy 3 and code-rod dystrophy 14. provided by RefSeq, Jul 2020]

ENSG00000290147 (HGNC:56129): (GUCA1ANB-GUCA1A readthrough) This locus represents naturally occurring readthrough transcription between the neighboring GUCA1ANB (GUCA1A neighbor) and GUCA1A (guanylate cyclase activator 1A) genes on chromosome 6. The readthrough transcript encodes the same protein as GUCA1A. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-42173588-A-G is Benign according to our data. Variant chr6-42173588-A-G is described in ClinVar as [Benign]. Clinvar id is 356691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCA1A	NM_001384910.1	c.-26A>G		5_prime_UTR_variant	Exon 1 of 4	ENST00000372958.2	NP_001371839.1
GUCA1ANB-GUCA1A	NM_000409.5	c.-26A>G		5_prime_UTR_variant	Exon 3 of 6		NP_000400.2
GUCA1ANB-GUCA1A	NM_001319061.2	c.-26A>G		5_prime_UTR_variant	Exon 3 of 6		NP_001305990.1
GUCA1ANB-GUCA1A	NM_001319062.2	c.-26A>G		5_prime_UTR_variant	Exon 2 of 5		NP_001305991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCA1A	ENST00000372958	c.-26A>G		5_prime_UTR_variant	Exon 1 of 4	1	NM_001384910.1	ENSP00000362049.1
ENSG00000290147	ENST00000654459	c.-26A>G		5_prime_UTR_variant	Exon 2 of 5			ENSP00000499539.1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20274 AN: 152134 Hom.: 4410 Cov.: 33

Gnomad AFR AF: 0.456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0606

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.0361 AC: 9069 AN: 250898 Hom.: 1736 AF XY: 0.0269 AC XY: 3646 AN XY: 135652

Gnomad AFR exome AF: 0.460

Gnomad AMR exome AF: 0.0301

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00299

Gnomad OTH exome AF: 0.0211

GnomAD4 exome AF: 0.0151 AC: 21749 AN: 1440254 Hom.: 3958 Cov.: 28 AF XY: 0.0132 AC XY: 9469 AN XY: 717862

Gnomad4 AFR exome AF: 0.470

Gnomad4 AMR exome AF: 0.0340

Gnomad4 ASJ exome AF: 0.00276

Gnomad4 EAS exome AF: 0.000429

Gnomad4 SAS exome AF: 0.00181

Gnomad4 FIN exome AF: 0.0000752

Gnomad4 NFE exome AF: 0.00192

Gnomad4 OTH exome AF: 0.0358

GnomAD4 genome AF: 0.134 AC: 20341 AN: 152252 Hom.: 4430 Cov.: 33 AF XY: 0.129 AC XY: 9618 AN XY: 74466

Gnomad4 AFR AF: 0.456

Gnomad4 AMR AF: 0.0605

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00328

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0184 Hom.: 655

Bravo AF: 0.152

Asia WGS AF: 0.0330 AC: 115 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cone dystrophy 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.2
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6937603; hg19: chr6-42141326;