chr7-32551377-A-G

Position:

• chr7-32551377-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015060.3(AVL9):​c.416A>G​(p.His139Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AVL9 NM_015060.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

AVL9 (HGNC:28994): (AVL9 cell migration associated) Involved in cell migration. Located in recycling endosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AVL9	NM_015060.3	c.416A>G	p.His139Arg	missense_variant	5/16	ENST00000318709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AVL9	ENST00000318709.9	c.416A>G	p.His139Arg	missense_variant	5/16	2	NM_015060.3	P1
AVL9	ENST00000409301.5	c.416A>G	p.His139Arg	missense_variant	5/15	5
AVL9	ENST00000446718.1	c.209A>G	p.His70Arg	missense_variant	4/13	5
AVL9	ENST00000485228.1	n.421A>G		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459744 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726380

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.416A>G (p.H139R) alteration is located in exon 5 (coding exon 5) of the AVL9 gene. This alteration results from a A to G substitution at nucleotide position 416, causing the histidine (H) at amino acid position 139 to be replaced by an arginine (R). 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	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.4	D;D;.;N
REVEL	Uncertain	0.46
Sift	Benign	0.094	T;T;.;T
Sift4G	Benign	0.27	T;T;.;D
Polyphen		0.99	D;.;.;.
Vest4		0.73
MutPred		0.36		Loss of catalytic residue at I137 (P = 0.1013);Loss of catalytic residue at I137 (P = 0.1013);Loss of catalytic residue at I137 (P = 0.1013);.;
MVP		0.67
MPC		0.31
ClinPred		0.90	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs905373246; hg19: chr7-32590989; COSMIC: COSV59466126;