Genetic Variant ENST00000546983.2:n.373+3679G>A (chr14-36517098-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000546983.2(SFTA3):n.373+1887C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000988 in 1,012,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.9e-7 ( 0 hom. )

Consequence

SFTA3
ENST00000546983.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.855

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000546983.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NKX2-1	NM_001079668.3	MANE Select	c.*180C>A	3_prime_UTR	Exon 3 of 3	NP_001073136.1
NKX2-1	NM_003317.4		c.*180C>A	3_prime_UTR	Exon 2 of 2	NP_003308.1
SFTA3	NR_161364.1		n.89+2370C>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NKX2-1	ENST00000354822.7	TSL:1 MANE Select	c.*180C>A	3_prime_UTR	Exon 3 of 3	ENSP00000346879.6
NKX2-1	ENST00000498187.6	TSL:1	c.*180C>A	3_prime_UTR	Exon 2 of 2	ENSP00000429607.2
SFTA3	ENST00000546983.2	TSL:4	n.373+1887C>A	intron	N/A	ENSP00000449302.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.88e-7

AC:

AN:

1012284

Hom.:

Cov.:

AF XY:

0.00000203

AC XY:

AN XY:

493418

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

21674

American (AMR)

AF:

0.00

AC:

AN:

12852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15764

East Asian (EAS)

AF:

0.00

AC:

AN:

28048

South Asian (SAS)

AF:

0.00

AC:

AN:

44194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28746

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2924

European-Non Finnish (NFE)

AF:

0.00000123

AC:

AN:

815148

Other (OTH)

AF:

0.00

AC:

AN:

42934

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.43

(source)

DANN

Benign

0.46

PhyloP100

-0.85

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over