chr7-117422276-C-T

Variant names:

• chr7-117422276-C-T
• rs779045591
• NM_130768.3:c.289G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_130768.3(ASZ1):​c.289G>A​(p.Val97Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ASZ1 NM_130768.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

Genes affected

ASZ1 (HGNC:1350): (ankyrin repeat, SAM and basic leucine zipper domain containing 1) Predicted to be involved in gamete generation and piRNA metabolic process. Predicted to be located in cytoplasm. Predicted to be active in pi-body. [provided by Alliance of Genome Resources, Apr 2022]

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

ACMG classification

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=0.13697979).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASZ1	NM_130768.3	c.289G>A	p.Val97Ile	missense_variant	Exon 3 of 13	ENST00000284629.7	NP_570124.1
ASZ1	NM_001301821.2	c.289G>A	p.Val97Ile	missense_variant	Exon 3 of 13		NP_001288750.1
ASZ1	NM_001301822.2	c.-224G>A		5_prime_UTR_variant	Exon 3 of 12		NP_001288751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASZ1	ENST00000284629.7	c.289G>A	p.Val97Ile	missense_variant	Exon 3 of 13	1	NM_130768.3	ENSP00000284629.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251334 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461592 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.289G>A (p.V97I) alteration is located in exon 3 (coding exon 3) of the ASZ1 gene. This alteration results from a G to A substitution at nucleotide position 289, causing the valine (V) at amino acid position 97 to be replaced by an isoleucine (I). 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	0.078
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.041	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.12	N;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.54	N;N
REVEL	Benign	0.060
Sift	Benign	0.35	T;T
Sift4G	Benign	0.25	T;.
Polyphen		0.0040	B;.
Vest4		0.17
MutPred		0.48		Loss of stability (P = 0.1633);.;
MVP		0.24
MPC		0.043
ClinPred		0.081	T
GERP RS		3.4
Varity_R		0.030
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs779045591; hg19: chr7-117062330;