NM_130768.3:c.1276-1422G>T

Variant names:

• chr7-117365170-C-A
• rs9886209
• NM_130768.3:c.1276-1422G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_130768.3(ASZ1):​c.1276-1422G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 152,054 control chromosomes in the GnomAD database, including 5,110 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (5110 hom., cov: 32)
• Consequence: ASZ1 NM_130768.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 6 publications found

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]

CFTR Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130768.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASZ1	NM_130768.3	MANE Select	c.1276-1422G>T		intron	N/A	NP_570124.1	Q8WWH4-1
	ASZ1	NM_001301821.2		c.1249-1422G>T		intron	N/A	NP_001288750.1	Q8WWH4-2
	ASZ1	NM_001301822.2		c.652-1422G>T		intron	N/A	NP_001288751.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASZ1	ENST00000284629.7	TSL:1 MANE Select	c.1276-1422G>T		intron	N/A	ENSP00000284629.2	Q8WWH4-1
	ASZ1	ENST00000450714.2	TSL:1	n.*717-1422G>T		intron	N/A	ENSP00000389791.2	F8WDQ2
	CFTR	ENST00000673785.1		c.-491+64140C>A		intron	N/A	ENSP00000501235.1	A0A669KBE8

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38518 AN: 151936 Hom.: 5111 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00481

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.255

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.253 AC: 38543 AN: 152054 Hom.: 5110 Cov.: 32 AF XY: 0.251 AC XY: 18659 AN XY: 74306

African (AFR) AF: 0.253 AC: 10486 AN: 41484

American (AMR) AF: 0.229 AC: 3498 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 628 AN: 3470

East Asian (EAS) AF: 0.00482 AC: 25 AN: 5182

South Asian (SAS) AF: 0.171 AC: 825 AN: 4824

European-Finnish (FIN) AF: 0.316 AC: 3335 AN: 10552

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18911 AN: 67966

Other (OTH) AF: 0.255 AC: 537 AN: 2108

Alfa AF: 0.224 Hom.: 1176

Bravo AF: 0.243

Asia WGS AF: 0.104 AC: 364 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.67
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9886209; hg19: chr7-117005224;