rs199885693

Variant names:

• chr6-42173698-T-A
• rs199885693
• NM_001384910.1:c.85T>A

Your query was ambiguous. Multiple possible variants found:

• chr6-42173698-T-A
• chr6-42173698-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001384910.1(GUCA1A):​c.85T>A​(p.Cys29Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C29Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GUCA1A NM_001384910.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

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]

GUCA1ANB-GUCA1A (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

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a chain Guanylyl cyclase-activating protein 1 (size 199) in uniprot entity GUC1A_HUMAN there are 34 pathogenic changes around while only 8 benign (81%) in NM_001384910.1
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Trascript score misZ: 0.22619 (below the threshold of 3.09). GenCC associations: The gene is linked to cone dystrophy 3, cone-rod dystrophy 14, hereditary macular dystrophy, cone dystrophy, central areolar choroidal dystrophy, cone-rod dystrophy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384910.1. 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
	GUCA1A	NM_001384910.1	MANE Select	c.85T>A	p.Cys29Ser	missense	Exon 1 of 4	NP_001371839.1	P43080
	GUCA1ANB-GUCA1A	NM_000409.5		c.85T>A	p.Cys29Ser	missense	Exon 3 of 6	NP_000400.2
	GUCA1ANB-GUCA1A	NM_001319061.2		c.85T>A	p.Cys29Ser	missense	Exon 3 of 6	NP_001305990.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCA1A	ENST00000372958.2	TSL:1 MANE Select	c.85T>A	p.Cys29Ser	missense	Exon 1 of 4	ENSP00000362049.1	P43080
	GUCA1ANB-GUCA1A	ENST00000654459.1		c.85T>A	p.Cys29Ser	missense	Exon 2 of 5	ENSP00000499539.1
	GUCA1ANB-GUCA1A	ENST00000703265.1		n.*320T>A		non_coding_transcript_exon	Exon 3 of 4	ENSP00000515250.1	A6PVH5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461560 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727102

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111716

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	26
DANN	Benign	0.96
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Uncertain	0.62
Sift	Benign	0.22	T
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.76		Gain of disorder (P = 0.0046)
MVP		0.78
MPC		0.97
ClinPred		0.99	D
GERP RS		5.8
PromoterAI		0.0015	Neutral
Varity_R		0.77
gMVP		0.71
Mutation Taster		=9/91	disease causing

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: rs199885693; hg19: chr6-42141436;