NM_001216.3:c.97G>A

Variant names:

• chr9-35674056-G-A
• rs2071676
• NM_001216.3:c.97G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001216.3(CA9):​c.97G>A​(p.Val33Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,613,758 control chromosomes in the GnomAD database, including 104,381 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.30 (8113 hom., cov: 32)
  • Exomes 𝑓: 0.36 (96268 hom.)
• Consequence: CA9 NM_001216.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.480
• Publications: 46 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.030832E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001216.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA9	NM_001216.3	MANE Select	c.97G>A	p.Val33Met	missense	Exon 1 of 11	NP_001207.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA9	ENST00000378357.9	TSL:1 MANE Select	c.97G>A	p.Val33Met	missense	Exon 1 of 11	ENSP00000367608.4
	ARHGEF39	ENST00000490638.5	TSL:1	n.-341C>T		non_coding_transcript_exon	Exon 1 of 12	ENSP00000436756.1
	ARHGEF39	ENST00000490638.5	TSL:1	n.-341C>T		5_prime_UTR	Exon 1 of 12	ENSP00000436756.1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46123 AN: 151984 Hom.: 8108 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.326

GnomAD2 exomes AF: 0.372 AC: 93577 AN: 251290 AF XY: 0.377

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.435

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.501

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.349

GnomAD4 exome AF: 0.359 AC: 524460 AN: 1461656 Hom.: 96268 Cov.: 42 AF XY: 0.362 AC XY: 263043 AN XY: 727146

African (AFR) AF: 0.103 AC: 3462 AN: 33480

American (AMR) AF: 0.430 AC: 19240 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 9568 AN: 26134

East Asian (EAS) AF: 0.475 AC: 18865 AN: 39694

South Asian (SAS) AF: 0.423 AC: 36448 AN: 86254

European-Finnish (FIN) AF: 0.403 AC: 21499 AN: 53408

Middle Eastern (MID) AF: 0.389 AC: 2241 AN: 5768

European-Non Finnish (NFE) AF: 0.353 AC: 392164 AN: 1111812

Other (OTH) AF: 0.347 AC: 20973 AN: 60394

GnomAD4 genome AF: 0.303 AC: 46125 AN: 152102 Hom.: 8113 Cov.: 32 AF XY: 0.309 AC XY: 23006 AN XY: 74344

African (AFR) AF: 0.111 AC: 4605 AN: 41538

American (AMR) AF: 0.374 AC: 5717 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1222 AN: 3472

East Asian (EAS) AF: 0.486 AC: 2499 AN: 5144

South Asian (SAS) AF: 0.431 AC: 2076 AN: 4816

European-Finnish (FIN) AF: 0.406 AC: 4300 AN: 10580

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.360 AC: 24492 AN: 67952

Other (OTH) AF: 0.324 AC: 686 AN: 2116

Alfa AF: 0.339 Hom.: 16065

Bravo AF: 0.292

ESP6500AA AF: 0.115 AC: 507

ESP6500EA AF: 0.348 AC: 2993

ExAC AF: 0.362 AC: 43914

Asia WGS AF: 0.375 AC: 1306 AN: 3478

EpiCase AF: 0.352

EpiControl AF: 0.349

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.00080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.48
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.72	P
Vest4		0.22
MPC		0.15
ClinPred		0.020	T
GERP RS		3.1
PromoterAI		-0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.17
Mutation Taster		=99/1	polymorphism (auto)

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: rs2071676; hg19: chr9-35674053; COSMIC: COSV65675780; COSMIC: COSV65675780;