7-117548796-G-T

Variant names:

• chr7-117548796-G-T
• rs79074685
• NM_000492.4:c.1365G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000492.4(CFTR):​c.1365G>T​(p.Ala455Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A455A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -1.15
• Publications: 12 publications found

Genes affected

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-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 7-117548796-G-T is Benign according to our data. Variant chr7-117548796-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193593.
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. 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
	CFTR	NM_000492.4	MANE Select	c.1365G>T	p.Ala455Ala	synonymous	Exon 10 of 27	NP_000483.3
	CFTR-AS1	NR_149084.1		n.222-6257C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1365G>T	p.Ala455Ala	synonymous	Exon 10 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.1365G>T	p.Ala455Ala	synonymous	Exon 10 of 27	ENSP00000514471.1
	CFTR	ENST00000889206.1		c.1365G>T	p.Ala455Ala	synonymous	Exon 10 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 225 AN: 119138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000698

Gnomad EAS AF: 0.00147

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00476

Gnomad NFE AF: 0.00139

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000479 AC: 11 AN: 229864 AF XY: 0.0000562

Gnomad AFR exome AF: 0.0000695

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000147

Gnomad NFE exome AF: 0.0000689

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000431 AC: 61 AN: 1415138 Hom.: 0 Cov.: 35 AF XY: 0.0000469 AC XY: 33 AN XY: 704042

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000937 AC: 3 AN: 32018

American (AMR) AF: 0.0000466 AC: 2 AN: 42934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24518

East Asian (EAS) AF: 0.0000546 AC: 2 AN: 36624

South Asian (SAS) AF: 0.0000353 AC: 3 AN: 84932

European-Finnish (FIN) AF: 0.000119 AC: 6 AN: 50466

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5462

European-Non Finnish (NFE) AF: 0.0000342 AC: 37 AN: 1080734

Other (OTH) AF: 0.000122 AC: 7 AN: 57450

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00191 AC: 228 AN: 119204 Hom.: 0 Cov.: 32 AF XY: 0.00220 AC XY: 127 AN XY: 57738

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00142 AC: 46 AN: 32332

American (AMR) AF: 0.00275 AC: 31 AN: 11278

Ashkenazi Jewish (ASJ) AF: 0.000698 AC: 2 AN: 2866

East Asian (EAS) AF: 0.00172 AC: 7 AN: 4062

South Asian (SAS) AF: 0.00167 AC: 6 AN: 3588

European-Finnish (FIN) AF: 0.00800 AC: 57 AN: 7122

Middle Eastern (MID) AF: 0.00490 AC: 1 AN: 204

European-Non Finnish (NFE) AF: 0.00141 AC: 78 AN: 55372

Other (OTH) AF: 0.00 AC: 0 AN: 1602

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0297 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Cystic fibrosis (3)
-	-	2	not specified (2)
-	1	-	CFTR-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.13
DANN	Benign	0.56
PhyloP100		-1.1
Mutation Taster		=97/3	polymorphism

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: rs79074685; hg19: chr7-117188850; COSMIC: COSV50042423;