Genetic Variant NFS1:c.-9A>T (chr20-35699297-T-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_021100.5(NFS1):c.-9A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,400,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

NFS1
NM_021100.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -3.23

Publications

0 publications found

Variant links:

Genes affected

NFS1 (HGNC:15910): (NFS1 cysteine desulfurase) Iron-sulfur clusters are required for the function of many cellular enzymes. The proteins encoded by this gene supply inorganic sulfur to these clusters by removing the sulfur from cysteine, creating alanine in the process. This gene uses alternate in-frame translation initiation sites to generate mitochondrial forms and cytoplasmic/nuclear forms. Selection of the alternative initiation sites is determined by the cytosolic pH. The encoded proteins belong to the class-V family of pyridoxal phosphate-dependent aminotransferases. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2010]

NFS1 links:

ROMO1 (HGNC:16185): (reactive oxygen species modulator 1) The protein encoded by this gene is a mitochondrial membrane protein that is responsible for increasing the level of reactive oxygen species (ROS) in cells. The protein also has antimicrobial activity against a variety of bacteria by inducing bacterial membrane breakage. [provided by RefSeq, Nov 2014]

ROMO1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 20-35699297-T-A is Benign according to our data. Variant chr20-35699297-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3046508.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021100.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NFS1	NM_021100.5	MANE Select	c.-9A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	NP_066923.3
NFS1	NM_021100.5	MANE Select	c.-9A>T	5_prime_UTR	Exon 1 of 13	NP_066923.3
NFS1	NM_001198989.2		c.-9A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001185918.1	Q9Y697-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NFS1	ENST00000374092.9	TSL:1 MANE Select	c.-9A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	ENSP00000363205.3	Q9Y697-1
NFS1	ENST00000306750.3	TSL:1	c.-9A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000304740.3	Q8WV90
NFS1	ENST00000374092.9	TSL:1 MANE Select	c.-9A>T	5_prime_UTR	Exon 1 of 13	ENSP00000363205.3	Q9Y697-1

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00499

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000408

AC:

AN:

22064

AF XY:

0.000414

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000419

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00422

Gnomad NFE exome

AF:

0.000568

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000211

AC:

264

AN:

1248412

Hom.:

Cov.:

AF XY:

0.000198

AC XY:

120

AN XY:

604616

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24404

American (AMR)

AF:

0.000140

AC:

AN:

14270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17814

East Asian (EAS)

AF:

0.00

AC:

AN:

29258

South Asian (SAS)

AF:

0.00

AC:

AN:

60270

European-Finnish (FIN)

AF:

0.00361

AC:

108

AN:

29902

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3518

European-Non Finnish (NFE)

AF:

0.000142

AC:

144

AN:

1017296

Other (OTH)

AF:

0.000193

AC:

AN:

51680

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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

AF:

0.000473

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00499

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68016

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000293

Hom.:

Bravo

AF:

0.000166

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

NFS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.71

(source)

DANN

Benign

0.48

PhyloP100

-3.2

PromoterAI

0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=259/41

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over