14-36516842-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 2.34

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 1149 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
NKX2-1	NM_001079668.3 linkuse as main transcript	c.*436A>C	3_prime_UTR_variant	3/3	ENST00000354822.7
SFTA3	NR_161364.1 linkuse as main transcript	n.89+2626A>C	intron_variant, non_coding_transcript_variant
NKX2-1	NM_003317.4 linkuse as main transcript	c.*436A>C	3_prime_UTR_variant	2/2
SFTA3	NR_161365.1 linkuse as main transcript	n.89+2626A>C	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-1	ENST00000354822.7 linkuse as main transcript	c.*436A>C	3_prime_UTR_variant	3/3	1	NM_001079668.3	P4	P43699-3
NKX2-1	ENST00000498187.6 linkuse as main transcript	c.*436A>C	3_prime_UTR_variant	2/2	1		A1	P43699-1
	ENST00000634305.1 linkuse as main transcript	n.322+68005T>G	intron_variant, non_coding_transcript_variant		5
NKX2-1	ENST00000518149.5 linkuse as main transcript	c.*436A>C	3_prime_UTR_variant	3/3	5		A1	P43699-1

Frequencies

GnomAD3 genomes

AF:

0.00756

AC:

1149

AN:

151950

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

38918

show subpopulations

Gnomad4 AFR exome

AF:

0.0242

Gnomad4 AMR exome

AF:

0.00155

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000191

Gnomad4 OTH exome

AF:

0.00333

GnomAD4 genome

AF:

0.00758

AC:

1153

AN:

152062

Hom.:

Cov.:

AF XY:

0.00738

AC XY:

549

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0265

Gnomad4 AMR

AF:

0.00236

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00570

Alfa

AF:

0.00446

Hom.:

Bravo

AF:

0.00907

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Brain-lung-thyroid syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

Cadd

Benign

Dann

Benign

0.87

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over