7-117422293-T-C

Position:

• chr7-117422293-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_130768.3(ASZ1):​c.272A>G​(p.Asn91Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: ASZ1 NM_130768.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.52

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33544934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASZ1	NM_130768.3	c.272A>G	p.Asn91Ser	missense_variant	3/13	ENST00000284629.7
ASZ1	NM_001301821.2	c.272A>G	p.Asn91Ser	missense_variant	3/13
ASZ1	NM_001301822.2	c.-241A>G		5_prime_UTR_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASZ1	ENST00000284629.7	c.272A>G	p.Asn91Ser	missense_variant	3/13	1	NM_130768.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251408 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1461576 Hom.: 0 Cov.: 30 AF XY: 0.0000385 AC XY: 28 AN XY: 727106

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000630

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74486

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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

Mar 28, 2024

The c.272A>G (p.N91S) alteration is located in exon 3 (coding exon 3) of the ASZ1 gene. This alteration results from a A to G substitution at nucleotide position 272, causing the asparagine (N) at amino acid position 91 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.92	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.1	N;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.053	T;.
Polyphen		1.0	D;.
Vest4		0.63
MutPred		0.68		Loss of catalytic residue at N91 (P = 0.2233);.;
MVP		0.73
MPC		0.29
ClinPred		0.15	T
GERP RS		5.6
Varity_R		0.21
gMVP		0.40

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: rs558179484; hg19: chr7-117062347;