14-36516985-A-AC

Variant names:

• chr14-36516985-A-AC
• rs140427692
• NM_001079668.3:c.*292dupG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001079668.3(NKX2-1):​c.*292dupG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 459,282 control chromosomes in the GnomAD database, including 11,758 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3711 hom., cov: 26)
  • Exomes 𝑓: 0.21 (8047 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

Genes affected

NKX2-1 (HGNC:11825): (NK2 homeobox 1) This gene encodes a protein initially identified as a thyroid-specific transcription factor. The encoded protein binds to the thyroglobulin promoter and regulates the expression of thyroid-specific genes but has also been shown to regulate the expression of genes involved in morphogenesis. Mutations and deletions in this gene are associated with benign hereditary chorea, choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress, and may be associated with thyroid cancer. Multiple transcript variants encoding different isoforms have been found for this gene. This gene shares the symbol/alias 'TTF1' with another gene, transcription termination factor 1, which plays a role in ribosomal gene transcription. [provided by RefSeq, Feb 2014]

SFTA3 (HGNC:):

SFTA3 (HGNC:18387): (surfactant associated 3) Involved in wound healing. Located in cytoplasm and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 14-36516985-A-AC is Benign according to our data. Variant chr14-36516985-A-AC is described in ClinVar as [Benign]. Clinvar id is 313131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.*292dupG		3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1
NKX2-1	NM_003317.4	c.*292dupG		3_prime_UTR_variant	Exon 2 of 2		NP_003308.1
SFTA3	NR_161364.1	n.89+2482dupG		intron_variant	Intron 1 of 4
SFTA3	NR_161365.1	n.89+2482dupG		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*292dupG		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.373+1999dupG		intron_variant	Intron 2 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes AF: 0.199 AC: 29932 AN: 150532 Hom.: 3712 Cov.: 26

Gnomad AFR AF: 0.0521

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.0891

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.213 AC: 65669 AN: 308644 Hom.: 8047 Cov.: 5 AF XY: 0.209 AC XY: 33109 AN XY: 158444

African (AFR) AF: 0.0417 AC: 385 AN: 9240

American (AMR) AF: 0.214 AC: 2074 AN: 9706

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 2907 AN: 10142

East Asian (EAS) AF: 0.0976 AC: 1877 AN: 19230

South Asian (SAS) AF: 0.137 AC: 4352 AN: 31826

European-Finnish (FIN) AF: 0.173 AC: 2410 AN: 13922

Middle Eastern (MID) AF: 0.221 AC: 298 AN: 1348

European-Non Finnish (NFE) AF: 0.243 AC: 47310 AN: 194830

Other (OTH) AF: 0.220 AC: 4056 AN: 18400

GnomAD4 genome AF: 0.199 AC: 29928 AN: 150638 Hom.: 3711 Cov.: 26 AF XY: 0.199 AC XY: 14654 AN XY: 73486

African (AFR) AF: 0.0520 AC: 2127 AN: 40888

American (AMR) AF: 0.242 AC: 3670 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1064 AN: 3466

East Asian (EAS) AF: 0.0893 AC: 457 AN: 5116

South Asian (SAS) AF: 0.145 AC: 693 AN: 4764

European-Finnish (FIN) AF: 0.240 AC: 2456 AN: 10232

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.274 AC: 18584 AN: 67732

Other (OTH) AF: 0.229 AC: 480 AN: 2092

Alfa AF: 0.220 Hom.: 370

Asia WGS AF: 0.144 AC: 502 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brain-lung-thyroid syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign hereditary chorea Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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: rs140427692; hg19: chr14-36986190; COSMIC: COSV61387320; COSMIC: COSV61387320;