chr14-36516734-C-T

Variant names:

• chr14-36516734-C-T
• rs886050478
• NM_001079668.3:c.*544G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001079668.3(NKX2-1):​c.*544G>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 0.0000258 in 232,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.471
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000264 (4/151702) while in subpopulation SAS AF = 0.000627 (3/4782). AF 95% confidence interval is 0.000171. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079668.3. 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
	NKX2-1	NM_001079668.3	MANE Select	c.*544G>A		3_prime_UTR	Exon 3 of 3	NP_001073136.1	P43699-3
	NKX2-1	NM_003317.4		c.*544G>A		3_prime_UTR	Exon 2 of 2	NP_003308.1	P43699-1
	SFTA3	NR_161364.1		n.89+2734G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-1	ENST00000354822.7	TSL:1 MANE Select	c.*544G>A		3_prime_UTR	Exon 3 of 3	ENSP00000346879.6	P43699-3
	NKX2-1	ENST00000498187.6	TSL:1	c.*544G>A		3_prime_UTR	Exon 2 of 2	ENSP00000429607.2	P43699-1
	SFTA3	ENST00000546983.2	TSL:4	n.373+2251G>A		intron	N/A	ENSP00000449302.2	F8VVG2

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151592 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000627

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 2 AN: 80982 Hom.: 0 Cov.: 0 AF XY: 0.0000268 AC XY: 1 AN XY: 37306

African (AFR) AF: 0.00 AC: 0 AN: 3862

American (AMR) AF: 0.000402 AC: 1 AN: 2488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5096

East Asian (EAS) AF: 0.00 AC: 0 AN: 11364

South Asian (SAS) AF: 0.00 AC: 0 AN: 704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 490

European-Non Finnish (NFE) AF: 0.0000201 AC: 1 AN: 49800

Other (OTH) AF: 0.00 AC: 0 AN: 6728

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151702 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74106

African (AFR) AF: 0.00 AC: 0 AN: 41348

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000627 AC: 3 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Benign hereditary chorea (1)
-	1	-	Brain-lung-thyroid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.9
DANN	Benign	0.90
PhyloP100		0.47

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: rs886050478; hg19: chr14-36985939;