9-35674184-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001216.3(CA9):​c.225G>T​(p.Glu75Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Consequence

CA9
NM_001216.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.26
Variant links:
Genes affected
CA9 (HGNC:1383): (carbonic anhydrase 9) 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. CA IX is a transmembrane protein and is one of only two tumor-associated carbonic anhydrase isoenzymes known. It is expressed in all clear-cell renal cell carcinoma, but is not detected in normal kidney or most other normal tissues. It may be involved in cell proliferation and transformation. This gene was mapped to 17q21.2 by fluorescence in situ hybridization, however, radiation hybrid mapping localized it to 9p13-p12. [provided by RefSeq, Jun 2014]
ARHGEF39 (HGNC:25909): (Rho guanine nucleotide exchange factor 39) Predicted to enable guanyl-nucleotide exchange factor activity. Involved in positive regulation of cell migration. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07956952).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CA9NM_001216.3 linkc.225G>T p.Glu75Asp missense_variant 1/11 ENST00000378357.9 NP_001207.2 Q16790A0A0S2Z3D0
CA9XM_047423849.1 linkc.225G>T p.Glu75Asp missense_variant 1/6 XP_047279805.1
CA9XM_047423850.1 linkc.225G>T p.Glu75Asp missense_variant 1/6 XP_047279806.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CA9ENST00000378357.9 linkc.225G>T p.Glu75Asp missense_variant 1/111 NM_001216.3 ENSP00000367608.4 Q16790
ARHGEF39ENST00000490638.5 linkn.-469C>A non_coding_transcript_exon_variant 1/121 ENSP00000436756.1 Q8N4T4-2
ARHGEF39ENST00000490638.5 linkn.-469C>A 5_prime_UTR_variant 1/121 ENSP00000436756.1 Q8N4T4-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 02, 2024The c.225G>T (p.E75D) alteration is located in exon 1 (coding exon 1) of the CA9 gene. This alteration results from a G to T substitution at nucleotide position 225, causing the glutamic acid (E) at amino acid position 75 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
12
DANN
Benign
0.75
DEOGEN2
Benign
0.098
T;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.077
N
LIST_S2
Benign
0.47
T;T
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.080
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.69
N;.
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.24
N;.
REVEL
Benign
0.094
Sift
Benign
0.066
T;.
Sift4G
Benign
0.11
T;T
Polyphen
0.0020
B;.
Vest4
0.18
MutPred
0.17
Gain of glycosylation at S71 (P = 0.3192);Gain of glycosylation at S71 (P = 0.3192);
MVP
0.54
MPC
0.14
ClinPred
0.054
T
GERP RS
-2.5
Varity_R
0.056
gMVP
0.043

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: chr9-35674181; API