8-85333547-G-T

Variant names:

• chr8-85333547-G-T
• NM_001128831.4:c.428C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001128831.4(CA1):​c.428C>A​(p.Ala143Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,442 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. A143V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CA1 NM_001128831.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.38

Genes affected

CA1 (HGNC:1368): (carbonic anhydrase 1) Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization. This CA1 gene is closely linked to the CA2 and CA3 genes on chromosome 8. It encodes a cytosolic protein that is found at the highest level in erythrocytes. Allelic variants of this gene have been described in some populations. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA1	NM_001128831.4	c.428C>A	p.Ala143Glu	missense_variant	Exon 5 of 8	ENST00000523022.6	NP_001122303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA1	ENST00000523022.6	c.428C>A	p.Ala143Glu	missense_variant	Exon 5 of 8	1	NM_001128831.4	ENSP00000429798.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459442 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T;D;D;D;D;T;T;.;T;.;T;T;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;.;.;.;D;D;D;D;D;D;D;.;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	5.4	.;H;H;H;H;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.7	.;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;.;D;.;.;.;.;D;.
Polyphen		1.0	.;D;D;D;D;.;.;.;.;.;.;.;.;.
Vest4		0.82
MutPred		0.72		.;Gain of disorder (P = 0.086);Gain of disorder (P = 0.086);Gain of disorder (P = 0.086);Gain of disorder (P = 0.086);.;.;Gain of disorder (P = 0.086);.;.;Gain of disorder (P = 0.086);Gain of disorder (P = 0.086);Gain of disorder (P = 0.086);Gain of disorder (P = 0.086);
MVP		0.91
MPC		0.23
ClinPred		1.0	D
GERP RS		2.2
Varity_R		0.97
gMVP		0.96

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-86245776;