14-36519624-A-G

Variant names:

• chr14-36519624-A-G
• rs374034707
• ENST00000498187.6:c.-267T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000498187.6(NKX2-1):​c.-267T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,530,792 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (51 hom.)
• Consequence: NKX2-1 ENST00000498187.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.57
• 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:):

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

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 14-36519624-A-G is Benign according to our data. Variant chr14-36519624-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1333071.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000998 (152/152364) while in subpopulation SAS AF = 0.0313 (151/4830). AF 95% confidence interval is 0.0272. There are 4 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 152 AD gene.

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

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

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-1	ENST00000498187.6	TSL:1	c.-267T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000429607.2	P43699-1
	NKX2-1	ENST00000498187.6	TSL:1	c.-267T>C		5_prime_UTR	Exon 1 of 2	ENSP00000429607.2	P43699-1
	NKX2-1	ENST00000354822.7	TSL:1 MANE Select	c.78-254T>C		intron	N/A	ENSP00000346879.6	P43699-3

Frequencies

GnomAD3 genomes AF: 0.00100 AC: 153 AN: 152246 Hom.: 4 Cov.: 33

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: 0.0314

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00457 AC: 600 AN: 131330 AF XY: 0.00596

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000192

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000396

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00161 AC: 2215 AN: 1378428 Hom.: 51 Cov.: 31 AF XY: 0.00233 AC XY: 1587 AN XY: 679986

African (AFR) AF: 0.000222 AC: 7 AN: 31526

American (AMR) AF: 0.00 AC: 0 AN: 35578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25058

East Asian (EAS) AF: 0.0000283 AC: 1 AN: 35364

South Asian (SAS) AF: 0.0261 AC: 2045 AN: 78366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32960

Middle Eastern (MID) AF: 0.000881 AC: 5 AN: 5674

European-Non Finnish (NFE) AF: 0.00000836 AC: 9 AN: 1076270

Other (OTH) AF: 0.00257 AC: 148 AN: 57632

GnomAD4 genome AF: 0.000998 AC: 152 AN: 152364 Hom.: 4 Cov.: 33 AF XY: 0.00152 AC XY: 113 AN XY: 74506

African (AFR) AF: 0.00 AC: 0 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.000189

Asia WGS AF: 0.0100 AC: 38 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.91
PhyloP100		3.6
PromoterAI		-0.0092	Neutral
Mutation Taster		=298/2	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: rs374034707; hg19: chr14-36988829;