3-108920536-A-G

Variant names:

• chr3-108920536-A-G
• rs754767660
• NM_005459.4:c.254T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005459.4(GUCA1C):​c.254T>C​(p.Met85Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,429,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. M85R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GUCA1C NM_005459.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.56
• Publications: 0 publications found

Genes affected

GUCA1C (HGNC:4680): (guanylate cyclase activator 1C) Predicted to enable calcium ion binding activity and calcium sensitive guanylate cyclase activator activity. Predicted to be involved in signal transduction. Predicted to be located in photoreceptor disc membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12179944).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005459.4. 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
	GUCA1C	NM_005459.4	MANE Select	c.254T>C	p.Met85Thr	missense	Exon 2 of 4	NP_005450.3
	GUCA1C	NM_001363884.1		c.254T>C	p.Met85Thr	missense	Exon 2 of 4	NP_001350813.1	C9JNI2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCA1C	ENST00000261047.8	TSL:1 MANE Select	c.254T>C	p.Met85Thr	missense	Exon 2 of 4	ENSP00000261047.3	O95843-1
	GUCA1C	ENST00000393963.7	TSL:1	c.254T>C	p.Met85Thr	missense	Exon 2 of 4	ENSP00000377535.3	C9JNI2
	GUCA1C	ENST00000471108.1	TSL:2	c.254T>C	p.Met85Thr	missense	Exon 2 of 3	ENSP00000417761.1	C9J7M7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1429004 Hom.: 0 Cov.: 26 AF XY: 0.00000280 AC XY: 2 AN XY: 713170

African (AFR) AF: 0.00 AC: 0 AN: 32738

American (AMR) AF: 0.0000224 AC: 1 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 85582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082386

Other (OTH) AF: 0.0000169 AC: 1 AN: 59304

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.46	N
PhyloP100		6.6
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.11
Sift	Benign	0.064	T
Sift4G	Benign	0.44	T
Polyphen		0.0020	B
Vest4		0.11
MutPred		0.41		Loss of catalytic residue at V81 (P = 0.0892)
MVP		0.39
MPC		0.030
ClinPred		0.65	D
GERP RS		4.0
Varity_R		0.47
gMVP		0.40
Mutation Taster		=89/11	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: rs754767660; hg19: chr3-108639383;