14-36516842-T-G

Variant names:

• chr14-36516842-T-G
• rs79849967
• NM_001079668.3:c.*436A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001079668.3(NKX2-1):​c.*436A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 236,158 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0076 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (1 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.34
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 14-36516842-T-G is Benign according to our data. Variant chr14-36516842-T-G is described in ClinVar as [Benign]. Clinvar id is 313130.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00758 (1153/152062) while in subpopulation AFR AF = 0.0265 (1101/41470). AF 95% confidence interval is 0.0252. There are 15 homozygotes in GnomAd4. There are 549 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1153 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.*436A>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1
NKX2-1	NM_003317.4	c.*436A>C		3_prime_UTR_variant	Exon 2 of 2		NP_003308.1
SFTA3	NR_161364.1	n.89+2626A>C		intron_variant	Intron 1 of 4
SFTA3	NR_161365.1	n.89+2626A>C		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*436A>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.373+2143A>C		intron_variant	Intron 2 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes AF: 0.00756 AC: 1149 AN: 151950 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00576

GnomAD4 exome AF: 0.00149 AC: 125 AN: 84096 Hom.: 1 Cov.: 0 AF XY: 0.00123 AC XY: 48 AN XY: 38918

African (AFR) AF: 0.0242 AC: 96 AN: 3962

American (AMR) AF: 0.00155 AC: 4 AN: 2584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5176

East Asian (EAS) AF: 0.00 AC: 0 AN: 11398

South Asian (SAS) AF: 0.00 AC: 0 AN: 948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 290

Middle Eastern (MID) AF: 0.00201 AC: 1 AN: 498

European-Non Finnish (NFE) AF: 0.0000191 AC: 1 AN: 52340

Other (OTH) AF: 0.00333 AC: 23 AN: 6900

GnomAD4 genome AF: 0.00758 AC: 1153 AN: 152062 Hom.: 15 Cov.: 32 AF XY: 0.00738 AC XY: 549 AN XY: 74348

African (AFR) AF: 0.0265 AC: 1101 AN: 41470

American (AMR) AF: 0.00236 AC: 36 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67986

Other (OTH) AF: 0.00570 AC: 12 AN: 2104

Alfa AF: 0.00367 Hom.: 3

Bravo AF: 0.00907

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Brain-lung-thyroid syndrome Benign:1

Jan 12, 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 12, 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	-0.51
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		2.3
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: rs79849967; hg19: chr14-36986047;