NM_001079668.3:c.*209T>A

Variant names:

• chr14-36517069-A-T
• rs572546897
• NM_001079668.3:c.*209T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001079668.3(NKX2-1):​c.*209T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 834,346 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (6 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00700
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-36517069-A-T is Benign according to our data. Variant chr14-36517069-A-T is described in ClinVar as [Benign]. Clinvar id is 313134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00308 (461/149550) while in subpopulation AFR AF = 0.00801 (327/40816). AF 95% confidence interval is 0.0073. There are 3 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 461 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.*209T>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1
NKX2-1	NM_003317.4	c.*209T>A		3_prime_UTR_variant	Exon 2 of 2		NP_003308.1
SFTA3	NR_161364.1	n.89+2399T>A		intron_variant	Intron 1 of 4
SFTA3	NR_161365.1	n.89+2399T>A		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*209T>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.373+1916T>A		intron_variant	Intron 2 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 455 AN: 149440 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00791

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00128

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.00612

Gnomad FIN AF: 0.00139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000789

Gnomad OTH AF: 0.00148

GnomAD4 exome AF: 0.00360 AC: 2464 AN: 684796 Hom.: 6 Cov.: 11 AF XY: 0.00379 AC XY: 1282 AN XY: 338626

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

African (AFR) AF: 0.0109 AC: 181 AN: 16540

American (AMR) AF: 0.00352 AC: 43 AN: 12220

Ashkenazi Jewish (ASJ) AF: 0.00129 AC: 17 AN: 13180

East Asian (EAS) AF: 0.00371 AC: 93 AN: 25086

South Asian (SAS) AF: 0.0115 AC: 405 AN: 35160

European-Finnish (FIN) AF: 0.00295 AC: 67 AN: 22746

Middle Eastern (MID) AF: 0.00226 AC: 5 AN: 2212

European-Non Finnish (NFE) AF: 0.00292 AC: 1539 AN: 526316

Other (OTH) AF: 0.00364 AC: 114 AN: 31336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00308 AC: 461 AN: 149550 Hom.: 3 Cov.: 33 AF XY: 0.00317 AC XY: 231 AN XY: 72972

African (AFR) AF: 0.00801 AC: 327 AN: 40816

American (AMR) AF: 0.00127 AC: 19 AN: 14920

Ashkenazi Jewish (ASJ) AF: 0.000291 AC: 1 AN: 3440

East Asian (EAS) AF: 0.00271 AC: 14 AN: 5164

South Asian (SAS) AF: 0.00612 AC: 29 AN: 4738

European-Finnish (FIN) AF: 0.00139 AC: 14 AN: 10056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000789 AC: 53 AN: 67192

Other (OTH) AF: 0.00196 AC: 4 AN: 2044

Alfa AF: 0.00175 Hom.: 1

Bravo AF: 0.00317

Asia WGS AF: 0.0100 AC: 35 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NKX2-1: BS1, BS2 -

Brain-lung-thyroid syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Benign hereditary chorea Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.37
DANN	Benign	0.55
PhyloP100		0.0070
Mutation Taster		=100/0	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: rs572546897; hg19: chr14-36986274; COSMIC: COSV61387547; COSMIC: COSV61387547;