7-117384751-A-G

Variant names:

• chr7-117384751-A-G
• rs780891217
• NM_130768.3:c.662T>C

Variant summary

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

The NM_130768.3(ASZ1):​c.662T>C​(p.Ile221Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000471 in 1,611,986 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (1 hom.)
• Consequence: ASZ1 NM_130768.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.72

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASZ1	NM_130768.3	c.662T>C	p.Ile221Thr	missense_variant	Exon 6 of 13	ENST00000284629.7	NP_570124.1
ASZ1	NM_001301821.2	c.662T>C	p.Ile221Thr	missense_variant	Exon 6 of 13		NP_001288750.1
ASZ1	NM_001301822.2	c.38T>C	p.Ile13Thr	missense_variant	Exon 5 of 12		NP_001288751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASZ1	ENST00000284629.7	c.662T>C	p.Ile221Thr	missense_variant	Exon 6 of 13	1	NM_130768.3	ENSP00000284629.2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000763 AC: 19 AN: 249014 Hom.: 0 AF XY: 0.0000594 AC XY: 8 AN XY: 134618

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1459834 Hom.: 1 Cov.: 30 AF XY: 0.0000358 AC XY: 26 AN XY: 726238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74332

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000666 Hom.: 0

Bravo AF: 0.000302

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.662T>C (p.I221T) alteration is located in exon 6 (coding exon 6) of the ASZ1 gene. This alteration results from a T to C substitution at nucleotide position 662, causing the isoleucine (I) at amino acid position 221 to be replaced by a threonine (T). 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	0.19
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.036	D
Polyphen		0.95	P
Vest4		0.78
MutPred		0.38		Gain of phosphorylation at I221 (P = 0.031);
MVP		0.73
MPC		0.088
ClinPred		0.12	T
GERP RS		4.7
Varity_R		0.35
gMVP		0.33

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: rs780891217; hg19: chr7-117024805;