20-35672891-TG-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_021100.5(NFS1):c.1221-48del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,126,122 control chromosomes in the GnomAD database, including 30 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (23 hom.)
• Consequence: NFS1 NM_021100.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.687

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 -10 ACMG points.

• BP6: Variant 20-35672891-TG-T is Benign according to our data. Variant chr20-35672891-TG-T is described in ClinVar as [Likely_benign]. Clinvar id is 1316324.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00265 (403/152310) while in subpopulation EAS AF= 0.0458 (237/5180). AF 95% confidence interval is 0.041. There are 7 homozygotes in gnomad4. There are 256 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFS1	NM_021100.5	c.1221-48del		intron_variant		ENST00000374092.9
NFS1	NM_001198989.2	c.1068-48del		intron_variant
NFS1	NR_037570.3	n.1407-48del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFS1	ENST00000374092.9	c.1221-48del		intron_variant		1	NM_021100.5	P1

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 404 AN: 152192 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0458

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00530 AC: 1010 AN: 190432 Hom.: 17 AF XY: 0.00520 AC XY: 527 AN XY: 101442

Gnomad AFR exome AF: 0.0000664

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0449

Gnomad SAS exome AF: 0.000630

Gnomad FIN exome AF: 0.0131

Gnomad NFE exome AF: 0.000298

Gnomad OTH exome AF: 0.00204

GnomAD4 exome AF: 0.00190 AC: 1848 AN: 973812 Hom.: 23 Cov.: 13 AF XY: 0.00179 AC XY: 889 AN XY: 497868

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000606

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0294

Gnomad4 SAS exome AF: 0.000681

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.00213

GnomAD4 genome AF: 0.00265 AC: 403 AN: 152310 Hom.: 7 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74470

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0458

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0125

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000255 Hom.: 0

Bravo AF: 0.00185

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs148568959; hg19: chr20-34260813;