Genetic Variant NM_001079668.3:c.448C>T (chr14-36519000-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001079668.3(NKX2-1):c.448C>T(p.Pro150Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000707 in 1,414,088 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P150A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

NKX2-1
NM_001079668.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.42

Publications

0 publications found

Variant links:

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]

NKX2-1 links:

SFTA3 (HGNC:):

SFTA3 links:

SFTA3 (HGNC:18387): (surfactant associated 3) Involved in wound healing. Located in cytoplasm and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

SFTA3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-1	NM_001079668.3 link	c.448C>T	p.Pro150Ser	missense_variant	Exon 2 of 3	ENST00000354822.7	NP_001073136.1	P43699-3
NKX2-1	NM_003317.4 link	c.358C>T	p.Pro120Ser	missense_variant	Exon 1 of 2		NP_003308.1	P43699-1
SFTA3	NR_161364.1 link	n.89+468C>T		intron_variant	Intron 1 of 4
SFTA3	NR_161365.1 link	n.89+468C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-1	ENST00000354822.7 link	c.448C>T	p.Pro150Ser	missense_variant	Exon 2 of 3	1	NM_001079668.3	ENSP00000346879.6		P43699-3
SFTA3	ENST00000546983.2 link	n.358C>T		non_coding_transcript_exon_variant	Exon 2 of 4	4		ENSP00000449302.2		F8VVG2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1414088

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

701290

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31982

American (AMR)

AF:

0.00

AC:

AN:

40934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25256

East Asian (EAS)

AF:

0.00

AC:

AN:

37572

South Asian (SAS)

AF:

0.00

AC:

AN:

82518

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5218

European-Non Finnish (NFE)

AF:

9.14e-7

AC:

AN:

1094288

Other (OTH)

AF:

0.00

AC:

AN:

58712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

T;.;T;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

.;D;.;D

M_CAP

Pathogenic

0.49

MetaRNN

Uncertain

0.52

D;D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Uncertain

2.6

M;.;M;M

PhyloP100

6.4

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.5

D;D;D;D

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.40

MutPred

0.28

Gain of glycosylation at P120 (P = 0.0294);.;Gain of glycosylation at P120 (P = 0.0294);Gain of glycosylation at P120 (P = 0.0294);

MVP

0.82

ClinPred

0.99

GERP RS

4.0

Varity_R

0.87

gMVP

0.85

Mutation Taster

=26/74

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over