14-36517098-GAAAA-G

Variant names:

• chr14-36517098-GAAAA-G
• rs200848675
• NM_001079668.3:c.*176_*179delTTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001079668.3(NKX2-1):​c.*176_*179delTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,159,822 control chromosomes in the GnomAD database, including 36,317 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3600 hom., cov: 28)
  • Exomes 𝑓: 0.24 (32717 hom.)
• Consequence: NKX2-1 NM_001079668.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.25
• Publications: 2 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 -10 ACMG points.

• BP6: Variant 14-36517098-GAAAA-G is Benign according to our data. Variant chr14-36517098-GAAAA-G is described in ClinVar as [Benign]. Clinvar id is 1291743.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.*176_*179delTTTT		3_prime_UTR_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1
NKX2-1	NM_003317.4	c.*176_*179delTTTT		3_prime_UTR_variant	Exon 2 of 2		NP_003308.1
SFTA3	NR_161364.1	n.89+2366_89+2369delTTTT		intron_variant	Intron 1 of 4
SFTA3	NR_161365.1	n.89+2366_89+2369delTTTT		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.*176_*179delTTTT		3_prime_UTR_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.373+1883_373+1886delTTTT		intron_variant	Intron 2 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29331 AN: 150682 Hom.: 3602 Cov.: 28

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.0868

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.227

GnomAD4 exome AF: 0.236 AC: 238375 AN: 1009024 Hom.: 32717 AF XY: 0.236 AC XY: 115951 AN XY: 491768

African (AFR) AF: 0.0381 AC: 825 AN: 21660

American (AMR) AF: 0.219 AC: 2808 AN: 12804

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 4555 AN: 15718

East Asian (EAS) AF: 0.105 AC: 2940 AN: 27998

South Asian (SAS) AF: 0.132 AC: 5825 AN: 44114

European-Finnish (FIN) AF: 0.207 AC: 5938 AN: 28662

Middle Eastern (MID) AF: 0.217 AC: 634 AN: 2922

European-Non Finnish (NFE) AF: 0.253 AC: 205157 AN: 812364

Other (OTH) AF: 0.227 AC: 9693 AN: 42782

GnomAD4 genome AF: 0.194 AC: 29325 AN: 150798 Hom.: 3600 Cov.: 28 AF XY: 0.194 AC XY: 14253 AN XY: 73480

African (AFR) AF: 0.0504 AC: 2085 AN: 41372

American (AMR) AF: 0.238 AC: 3603 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1052 AN: 3460

East Asian (EAS) AF: 0.0870 AC: 449 AN: 5158

South Asian (SAS) AF: 0.142 AC: 678 AN: 4784

European-Finnish (FIN) AF: 0.222 AC: 2238 AN: 10064

Middle Eastern (MID) AF: 0.215 AC: 62 AN: 288

European-Non Finnish (NFE) AF: 0.272 AC: 18367 AN: 67552

Other (OTH) AF: 0.225 AC: 472 AN: 2094

Alfa AF: 0.0867 Hom.: 137

Asia WGS AF: 0.138 AC: 479 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs200848675; hg19: chr14-36986303; COSMIC: COSV61389578; COSMIC: COSV61389578;