20-35681303-G-T

Variant names:

• chr20-35681303-G-T
• rs6058296
• NM_021100.5:c.656-432C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021100.5(NFS1):​c.656-432C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 152,026 control chromosomes in the GnomAD database, including 1,640 homozygotes. 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: 𝑓 0.15 (1640 hom., cov: 32)
• Consequence: NFS1 NM_021100.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.62
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation deficiency 52

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFS1	NM_021100.5	c.656-432C>A		intron_variant	Intron 6 of 12	ENST00000374092.9	NP_066923.3
NFS1	NM_001198989.2	c.503-432C>A		intron_variant	Intron 5 of 11		NP_001185918.1
NFS1	NR_037570.3	n.842-432C>A		intron_variant	Intron 7 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFS1	ENST00000374092.9	c.656-432C>A		intron_variant	Intron 6 of 12	1	NM_021100.5	ENSP00000363205.3

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22319 AN: 151922 Hom.: 1640 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.0793

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.158

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.147 AC: 22324 AN: 152026 Hom.: 1640 Cov.: 32 AF XY: 0.146 AC XY: 10825 AN XY: 74286

African (AFR) AF: 0.173 AC: 7189 AN: 41492

American (AMR) AF: 0.138 AC: 2109 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 585 AN: 3470

East Asian (EAS) AF: 0.0792 AC: 410 AN: 5174

South Asian (SAS) AF: 0.156 AC: 753 AN: 4820

European-Finnish (FIN) AF: 0.140 AC: 1472 AN: 10508

Middle Eastern (MID) AF: 0.198 AC: 57 AN: 288

European-Non Finnish (NFE) AF: 0.136 AC: 9274 AN: 67984

Other (OTH) AF: 0.159 AC: 336 AN: 2112

Alfa AF: 0.136 Hom.: 1850

Bravo AF: 0.146

Asia WGS AF: 0.154 AC: 533 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.057
DANN	Benign	0.38
PhyloP100		-1.6
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: rs6058296; hg19: chr20-34269225;