rs566916288

Variant names:

• chr14-36516699-G-C
• rs566916288
• NM_001079668.3:c.*579C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001079668.3(NKX2-1):​c.*579C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 233,586 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (0 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.189
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-36516699-G-C is Benign according to our data. Variant chr14-36516699-G-C is described in ClinVar as Benign. ClinVar VariationId is 313124.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00353 (537/152314) while in subpopulation AFR AF = 0.0124 (514/41550). AF 95% confidence interval is 0.0115. There are 4 homozygotes in GnomAd4. There are 258 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 537 AD gene.

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.*579C>G		3_prime_UTR	Exon 3 of 3	NP_001073136.1	P43699-3
	NKX2-1	NM_003317.4		c.*579C>G		3_prime_UTR	Exon 2 of 2	NP_003308.1	P43699-1
	SFTA3	NR_161364.1		n.89+2769C>G		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.*579C>G		3_prime_UTR	Exon 3 of 3	ENSP00000346879.6	P43699-3
	NKX2-1	ENST00000498187.6	TSL:1	c.*579C>G		3_prime_UTR	Exon 2 of 2	ENSP00000429607.2	P43699-1
	SFTA3	ENST00000546983.2	TSL:4	n.373+2286C>G		intron	N/A	ENSP00000449302.2	F8VVG2

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 539 AN: 152196 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000886 AC: 72 AN: 81272 Hom.: 0 Cov.: 0 AF XY: 0.000801 AC XY: 30 AN XY: 37430

African (AFR) AF: 0.0124 AC: 48 AN: 3878

American (AMR) AF: 0.000400 AC: 1 AN: 2502

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 6 AN: 5110

East Asian (EAS) AF: 0.00 AC: 0 AN: 11390

South Asian (SAS) AF: 0.00 AC: 0 AN: 706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 478

Middle Eastern (MID) AF: 0.00204 AC: 1 AN: 490

European-Non Finnish (NFE) AF: 0.000100 AC: 5 AN: 49964

Other (OTH) AF: 0.00163 AC: 11 AN: 6754

GnomAD4 genome AF: 0.00353 AC: 537 AN: 152314 Hom.: 4 Cov.: 32 AF XY: 0.00346 AC XY: 258 AN XY: 74482

African (AFR) AF: 0.0124 AC: 514 AN: 41550

American (AMR) AF: 0.000980 AC: 15 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00406 Hom.: 1

Bravo AF: 0.00372

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

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	-0.87
CADD	Benign	0.41
DANN	Benign	0.76
PhyloP100		-0.19
Mutation Taster		=97/3	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: rs566916288; hg19: chr14-36985904;