chr14-36516817-C-CAA

Position:

• chr14-36516817-C-CAA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001079668.3(NKX2-1):​c.*460_*461insTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 0)
  • Exomes 𝑓: 0.018 (0 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.44

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00468 (666/142392) while in subpopulation SAS AF= 0.0132 (58/4406). AF 95% confidence interval is 0.0105. There are 3 homozygotes in gnomad4. There are 346 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 666 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-1	NM_001079668.3	c.*460_*461insTT		3_prime_UTR_variant	3/3	ENST00000354822.7
SFTA3	NR_161364.1	n.89+2650_89+2651insTT		intron_variant, non_coding_transcript_variant
NKX2-1	NM_003317.4	c.*460_*461insTT		3_prime_UTR_variant	2/2
SFTA3	NR_161365.1	n.89+2650_89+2651insTT		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*460_*461insTT		3_prime_UTR_variant	3/3	1	NM_001079668.3	P4
NKX2-1	ENST00000498187.6	c.*460_*461insTT		3_prime_UTR_variant	2/2	1		A1
	ENST00000634305.1	n.322+67994_322+67995dup		intron_variant, non_coding_transcript_variant		5
NKX2-1	ENST00000518149.5	c.*460_*461insTT		3_prime_UTR_variant	3/3	5		A1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 662 AN: 142334 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00460

Gnomad AMI AF: 0.0249

Gnomad AMR AF: 0.00442

Gnomad ASJ AF: 0.000598

Gnomad EAS AF: 0.00547

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00436

Gnomad OTH AF: 0.00761

GnomAD4 exome AF: 0.0181 AC: 1346 AN: 74446 Hom.: 0 Cov.: 0 AF XY: 0.0183 AC XY: 626 AN XY: 34288

Gnomad4 AFR exome AF: 0.0132

Gnomad4 AMR exome AF: 0.0147

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.0227

Gnomad4 SAS exome AF: 0.0174

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0178

Gnomad4 OTH exome AF: 0.0215

GnomAD4 genome AF: 0.00468 AC: 666 AN: 142392 Hom.: 3 Cov.: 0 AF XY: 0.00502 AC XY: 346 AN XY: 68882

Gnomad4 AFR AF: 0.00466

Gnomad4 AMR AF: 0.00441

Gnomad4 ASJ AF: 0.000598

Gnomad4 EAS AF: 0.00549

Gnomad4 SAS AF: 0.0132

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00436

Gnomad4 OTH AF: 0.00804

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Brain-lung-thyroid syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Benign hereditary chorea Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5807883; hg19: chr14-36986022;