rs201434579

Positions:

• chr7-117548743-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_000492.4(CFTR):​c.1312A>G​(p.Thr438Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 0.113

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:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028181374).
• BP6: Variant 7-117548743-A-G is Benign according to our data. Variant chr7-117548743-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193594.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1312A>G	p.Thr438Ala	missense_variant	10/27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.222-6204T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1312A>G	p.Thr438Ala	missense_variant	10/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.000207 AC: 47 AN: 227554 Hom.: 0 AF XY: 0.000202 AC XY: 25 AN XY: 123626

Gnomad AFR exome AF: 0.000285

Gnomad AMR exome AF: 0.0000610

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000577

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000105

Gnomad NFE exome AF: 0.000370

Gnomad OTH exome AF: 0.000178

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Alfa AF: 0.0263 Hom.: 0

ExAC AF: 0.00248 AC: 301

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 07, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CFTR p.Thr438Ala variant was not identified in the Cosmic or MutDB databases but was identified in dbSNP (ID: rs201434579), ClinVar (reported as a VUS by Emory and Illumina and benign by the Center for Pediatric Genomic Medicine at the Children's Mercy Hospital and Clinics), Clinvitae and LOVD 3.0. The variant was identified in control databases in 910 of 243424 chromosomes at a frequency of 0.003738 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 184 of 18116 chromosomes (freq: 0.01016), European (Finnish) in 195 of 20214 chromosomes (freq: 0.009647), Other in 46 of 6026 chromosomes (freq: 0.007634), European (non-Finnish) in 407 of 108932 chromosomes (freq: 0.003736), East Asian in 26 of 18052 chromosomes (freq: 0.00144), Latino in 42 of 33100 chromosomes (freq: 0.001269) and Ashkenazi Jewish in 10 of 9894 chromosomes (freq: 0.001011), but was not observed in the South Asian population. Trujillano et al. (2015) identified this variant in the heterozygous state in 1/177 cystic fibrosis patients but suggested the variant to be neutral (Trujillano_2015_PMID: 26436105). The p.Thr438 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

CFTR-related disorder Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 21, 2024	The CFTR c.1312A>G variant is predicted to result in the amino acid substitution p.Thr438Ala. This variant has been reported in a heterozygous state in an individual with cystic fibrosis although it is unknown if a second variant was detected (Trujillano et al. 2015. PMID: 26436105). This variant is reported in 1.0% of alleles in individuals of African descent in gnomAD; however, part of the data set did not pass the quality metrics so this data should be interpreted with caution. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cystic fibrosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Hereditary pancreatitis Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	6.9
DANN	Benign	0.84
DEOGEN2	Uncertain	0.48	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.71	N;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.31	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0	B;.
Vest4		0.15
MVP		0.79
MPC		0.0041
ClinPred		0.0093	T
GERP RS		-6.7
Varity_R		0.15
gMVP		0.68

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: rs201434579; hg19: chr7-117188797; COSMIC: COSV50041424;