20-35672958-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_021100.5(NFS1):c.1221-114A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 659,448 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (15 hom.)
• Consequence: NFS1 NM_021100.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.644

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=-0.88).
• BP6: Variant 20-35672958-T-A is Benign according to our data. Variant chr20-35672958-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 1316339.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0104 (1587/152230) while in subpopulation AFR AF= 0.0352 (1462/41542). AF 95% confidence interval is 0.0337. There are 21 homozygotes in gnomad4. There are 745 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFS1	NM_021100.5	c.1221-114A>T		intron_variant		ENST00000374092.9
NFS1	NM_001198989.2	c.1068-114A>T		intron_variant
NFS1	NR_037570.3	n.1407-114A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFS1	ENST00000374092.9	c.1221-114A>T		intron_variant		1	NM_021100.5	P1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1583 AN: 152112 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00718

GnomAD4 exome AF: 0.00162 AC: 824 AN: 507218 Hom.: 15 AF XY: 0.00136 AC XY: 366 AN XY: 268310

Gnomad4 AFR exome AF: 0.0358

Gnomad4 AMR exome AF: 0.00448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000205

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000425

Gnomad4 OTH exome AF: 0.00424

GnomAD4 genome AF: 0.0104 AC: 1587 AN: 152230 Hom.: 21 Cov.: 32 AF XY: 0.0100 AC XY: 745 AN XY: 74438

Gnomad4 AFR AF: 0.0352

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00688 Hom.: 5

Bravo AF: 0.0121

Asia WGS AF: 0.00318 AC: 12 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

Jul 26, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	3.1
Dann	Benign	0.73

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: rs73277231; hg19: chr20-34260880;