NM_021100.5:c.1221-48delC

Variant names:

• chr20-35672891-TG-T
• rs148568959
• NM_021100.5:c.1221-48delC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_021100.5(NFS1):​c.1221-48delC 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
• 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.1221-48delC		intron	N/A	NP_066923.3
	NFS1	NM_001198989.2		c.1068-48delC		intron	N/A	NP_001185918.1	Q9Y697-3
	NFS1	NR_037570.3		n.1407-48delC		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFS1	ENST00000374092.9	TSL:1 MANE Select	c.1221-48delC		intron	N/A	ENSP00000363205.3	Q9Y697-1
	ENSG00000272897	ENST00000541176.2	TSL:2	n.198-48delC		intron	N/A	ENSP00000443983.2	H0YGN5
	NFS1	ENST00000874539.1		c.1248-48delC		intron	N/A	ENSP00000544598.1

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

GnomAD2 exomes AF: 0.00530 AC: 1010 AN: 190432 AF XY: 0.00520

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 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

African (AFR) AF: 0.00 AC: 0 AN: 22850

American (AMR) AF: 0.0000606 AC: 2 AN: 33008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18936

East Asian (EAS) AF: 0.0294 AC: 1089 AN: 37058

South Asian (SAS) AF: 0.000681 AC: 45 AN: 66058

European-Finnish (FIN) AF: 0.0107 AC: 536 AN: 50296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4616

European-Non Finnish (NFE) AF: 0.000119 AC: 83 AN: 697422

Other (OTH) AF: 0.00213 AC: 93 AN: 43568

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41574

American (AMR) AF: 0.000131 AC: 2 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0458 AC: 237 AN: 5180

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4820

European-Finnish (FIN) AF: 0.0125 AC: 133 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000255 Hom.: 0

Bravo AF: 0.00185

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs148568959; hg19: chr20-34260813;