3-186057491-C-G

Variant names:

• chr3-186057491-C-G
• NM_004454.3:c.971G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004454.3(ETV5):​c.971G>C​(p.Gly324Ala) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ETV5 NM_004454.3 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.43

Genes affected

ETV5 (HGNC:3494): (ETS variant transcription factor 5) Enables DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in cellular response to oxidative stress; negative regulation of transcription by RNA polymerase II; and positive regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETV5	NM_004454.3	c.971G>C	p.Gly324Ala	missense_variant, splice_region_variant	Exon 10 of 13	ENST00000306376.10	NP_004445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETV5	ENST00000306376.10	c.971G>C	p.Gly324Ala	missense_variant, splice_region_variant	Exon 10 of 13	1	NM_004454.3	ENSP00000306894.5
ETV5	ENST00000434744.5	c.971G>C	p.Gly324Ala	missense_variant, splice_region_variant	Exon 10 of 13	1		ENSP00000413755.1
ETV5	ENST00000480706.1	n.145G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 5	3
ETV5	ENST00000433149.1	n.218-5360G>C		intron_variant	Intron 2 of 3	5		ENSP00000399707.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.971G>C (p.G324A) alteration is located in exon 10 (coding exon 9) of the ETV5 gene. This alteration results from a G to C substitution at nucleotide position 971, causing the glycine (G) at amino acid position 324 to be replaced by an alanine (A). 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	0.094
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	.;T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.50	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.071	T;T
Polyphen		0.45	P;P
Vest4		0.46
MutPred		0.72		Loss of disorder (P = 0.1244);Loss of disorder (P = 0.1244);
MVP		0.47
MPC		0.59
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.73
gMVP		0.55
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
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: chr3-185775280;