20-35669741-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021100.5(NFS1):c.1311-56T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.058 in 1,527,170 control chromosomes in the GnomAD database, including 3,662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.068 (431 hom., cov: 32)
  • Exomes 𝑓: 0.057 (3231 hom.)
• Consequence: NFS1 NM_021100.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.871

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-35669741-A-C is Benign according to our data. Variant chr20-35669741-A-C is described in ClinVar as [Benign]. Clinvar id is 676162.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFS1	NM_021100.5	c.1311-56T>G		intron_variant		ENST00000374092.9
NFS1	NM_001198989.2	c.1158-56T>G		intron_variant
NFS1	NR_037570.3	n.1497-56T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFS1	ENST00000374092.9	c.1311-56T>G		intron_variant		1	NM_021100.5	P1

Frequencies

GnomAD3 genomes AF: 0.0675 AC: 10269 AN: 152114 Hom.: 417 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.0524

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.0496

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0488

Gnomad OTH AF: 0.0584

GnomAD4 exome AF: 0.0569 AC: 78230 AN: 1374936 Hom.: 3231 AF XY: 0.0607 AC XY: 41816 AN XY: 688860

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.0267

Gnomad4 ASJ exome AF: 0.0607

Gnomad4 EAS exome AF: 0.0370

Gnomad4 SAS exome AF: 0.181

Gnomad4 FIN exome AF: 0.0511

Gnomad4 NFE exome AF: 0.0469

Gnomad4 OTH exome AF: 0.0623

GnomAD4 genome AF: 0.0677 AC: 10313 AN: 152234 Hom.: 431 Cov.: 32 AF XY: 0.0701 AC XY: 5216 AN XY: 74436

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0405

Gnomad4 ASJ AF: 0.0550

Gnomad4 EAS AF: 0.0521

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.0496

Gnomad4 NFE AF: 0.0488

Gnomad4 OTH AF: 0.0658

Alfa AF: 0.0372 Hom.: 40

Bravo AF: 0.0648

Asia WGS AF: 0.139 AC: 485 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.1
Dann	Benign	0.55

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

LitVar

Other links and lift over

dbSNP: rs6060546; hg19: chr20-34257663;