Genetic Variant ENST00000498187.6:c.-267T>G (chr14-36519624-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000498187.6(NKX2-1):c.-267T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,378,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

NKX2-1
ENST00000498187.6 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.57

Publications

0 publications found

Variant links:

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]

NKX2-1 links:

SFTA3 (HGNC:):

SFTA3 links:

NKX2-1-AS1 (HGNC:40585): (NKX2-1 antisense RNA 1)

NKX2-1-AS1 links:

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

SFTA3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000498187.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NKX2-1	NM_001079668.3	MANE Select	c.78-254T>G	intron	N/A	NP_001073136.1	P43699-3
NKX2-1-AS1	NR_103710.1		n.347A>C	non_coding_transcript_exon	Exon 1 of 2
NKX2-1	NM_003317.4		c.-267T>G	upstream_gene	N/A	NP_003308.1	P43699-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NKX2-1	ENST00000498187.6	TSL:1	c.-267T>G	5_prime_UTR	Exon 1 of 2	ENSP00000429607.2	P43699-1
NKX2-1	ENST00000354822.7	TSL:1 MANE Select	c.78-254T>G	intron	N/A	ENSP00000346879.6	P43699-3
NKX2-1	ENST00000522719.4	TSL:1	c.-158-12T>G	intron	N/A	ENSP00000429519.4	P43699-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.25e-7

AC:

AN:

1378428

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

679986

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31526

American (AMR)

AF:

0.00

AC:

AN:

35578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25058

East Asian (EAS)

AF:

0.00

AC:

AN:

35364

South Asian (SAS)

AF:

0.00

AC:

AN:

78366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32960

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

9.29e-7

AC:

AN:

1076270

Other (OTH)

AF:

0.00

AC:

AN:

57632

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

3.6

PromoterAI

0.025

Neutral

(source)

Mutation Taster

=298/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over