20-35672999-A-G

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.1221-155T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 152,336 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.013 (23 hom., cov: 32)
• Consequence: NFS1 NM_021100.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.214

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=-0.91).
• BP6: Variant 20-35672999-A-G is Benign according to our data. Variant chr20-35672999-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1317541.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0129 (1968/152336) while in subpopulation SAS AF= 0.0269 (130/4826). AF 95% confidence interval is 0.0232. There are 23 homozygotes in gnomad4. There are 922 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFS1	NM_021100.5	c.1221-155T>C		intron_variant		ENST00000374092.9
NFS1	NM_001198989.2	c.1068-155T>C		intron_variant
NFS1	NR_037570.3	n.1407-155T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFS1	ENST00000374092.9	c.1221-155T>C		intron_variant		1	NM_021100.5	P1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1966 AN: 152218 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0105

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

GnomAD4 genome AF: 0.0129 AC: 1968 AN: 152336 Hom.: 23 Cov.: 32 AF XY: 0.0124 AC XY: 922 AN XY: 74490

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.0160

Gnomad4 NFE AF: 0.0202

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0174 Hom.: 7

Bravo AF: 0.0116

Asia WGS AF: 0.00895 AC: 32 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 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	2.6
Dann	Benign	0.31

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: rs34621588; hg19: chr20-34260921;