rs1555349218

Variant names:

• chr14-36517849-T-G
• rs1555349218
• NM_001079668.3:c.635A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001079668.3(NKX2-1):​c.635A>C​(p.Gln212Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX2-1 NM_001079668.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.09
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001079668.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 14-36517849-T-G is Pathogenic according to our data. Variant chr14-36517849-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436016.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3	c.635A>C	p.Gln212Pro	missense_variant	Exon 3 of 3	ENST00000354822.7	NP_001073136.1
NKX2-1	NM_003317.4	c.545A>C	p.Gln182Pro	missense_variant	Exon 2 of 2		NP_003308.1
SFTA3	NR_161364.1	n.89+1619A>C		intron_variant	Intron 1 of 4
SFTA3	NR_161365.1	n.89+1619A>C		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7	c.635A>C	p.Gln212Pro	missense_variant	Exon 3 of 3	1	NM_001079668.3	ENSP00000346879.6
SFTA3	ENST00000546983.2	n.373+1136A>C		intron_variant	Intron 2 of 3	4		ENSP00000449302.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Brain-lung-thyroid syndrome Pathogenic:1

Jun 27, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D;.;D;D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	.;D;.;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;M;M
PhyloP100		6.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.90
MutPred		0.45		Loss of MoRF binding (P = 0.0488);.;Loss of MoRF binding (P = 0.0488);Loss of MoRF binding (P = 0.0488);
MVP		0.95
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.99
gMVP		0.96
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs1555349218; hg19: chr14-36987054;