chr20-35669375-T-C

Variant names:

• chr20-35669375-T-C
• rs17092960
• NM_021100.5:c.*247A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021100.5(NFS1):​c.*247A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 426,830 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (0 hom.)
• Consequence: NFS1 NM_021100.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.81
• Publications: 0 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

ENSG00000272897 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-35669375-T-C is Benign according to our data. Variant chr20-35669375-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1317877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00539 (821/152302) while in subpopulation AFR AF = 0.0186 (775/41562). AF 95% confidence interval is 0.0176. There are 18 homozygotes in GnomAd4. There are 399 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021100.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFS1	NM_021100.5	MANE Select	c.*247A>G		3_prime_UTR	Exon 13 of 13	NP_066923.3
	NFS1	NM_001198989.2		c.*247A>G		3_prime_UTR	Exon 12 of 12	NP_001185918.1	Q9Y697-3
	NFS1	NR_037570.3		n.1807A>G		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFS1	ENST00000374092.9	TSL:1 MANE Select	c.*247A>G		3_prime_UTR	Exon 13 of 13	ENSP00000363205.3	Q9Y697-1
	ENSG00000272897	ENST00000541176.2	TSL:2	n.287+3380A>G		intron	N/A	ENSP00000443983.2	H0YGN5
	NFS1	ENST00000874539.1		c.*247A>G		3_prime_UTR	Exon 13 of 13	ENSP00000544598.1

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 781 AN: 152184 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.000761 AC: 209 AN: 274528 Hom.: 0 Cov.: 0 AF XY: 0.000644 AC XY: 92 AN XY: 142792

African (AFR) AF: 0.0172 AC: 149 AN: 8658

American (AMR) AF: 0.00177 AC: 21 AN: 11868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9072

East Asian (EAS) AF: 0.00 AC: 0 AN: 20570

South Asian (SAS) AF: 0.0000433 AC: 1 AN: 23074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18218

Middle Eastern (MID) AF: 0.00161 AC: 2 AN: 1242

European-Non Finnish (NFE) AF: 0.0000242 AC: 4 AN: 165374

Other (OTH) AF: 0.00195 AC: 32 AN: 16452

GnomAD4 genome AF: 0.00539 AC: 821 AN: 152302 Hom.: 18 Cov.: 32 AF XY: 0.00536 AC XY: 399 AN XY: 74490

African (AFR) AF: 0.0186 AC: 775 AN: 41562

American (AMR) AF: 0.00209 AC: 32 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.00611

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.1
DANN	Benign	0.48
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism

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: rs17092960; hg19: chr20-34257297;