20-35699326-A-G

Variant names:

• chr20-35699326-A-G
• rs975021871
• NM_021100.5:c.-38T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021100.5(NFS1):​c.-38T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000806 in 1,240,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: NFS1 NM_021100.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.766
• 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]

ROMO1 (HGNC:16185): (reactive oxygen species modulator 1) The protein encoded by this gene is a mitochondrial membrane protein that is responsible for increasing the level of reactive oxygen species (ROS) in cells. The protein also has antimicrobial activity against a variety of bacteria by inducing bacterial membrane breakage. [provided by RefSeq, Nov 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

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.-38T>C		5_prime_UTR	Exon 1 of 13	NP_066923.3
	NFS1	NM_001198989.2		c.-38T>C		5_prime_UTR	Exon 1 of 12	NP_001185918.1	Q9Y697-3
	NFS1	NR_037570.3		n.27T>C		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFS1	ENST00000374092.9	TSL:1 MANE Select	c.-38T>C		5_prime_UTR	Exon 1 of 13	ENSP00000363205.3	Q9Y697-1
	ROMO1	ENST00000374078.5	TSL:1	c.-126A>G		5_prime_UTR	Exon 1 of 3	ENSP00000363191.1	P60602-1
	NFS1	ENST00000874539.1		c.-38T>C		5_prime_UTR	Exon 1 of 13	ENSP00000544598.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.06e-7 AC: 1 AN: 1240914 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 600486

African (AFR) AF: 0.00 AC: 0 AN: 24456

American (AMR) AF: 0.00 AC: 0 AN: 14382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17710

East Asian (EAS) AF: 0.00 AC: 0 AN: 29332

South Asian (SAS) AF: 0.00 AC: 0 AN: 60008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3480

European-Non Finnish (NFE) AF: 9.90e-7 AC: 1 AN: 1010262

Other (OTH) AF: 0.00 AC: 0 AN: 51392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.32
PhyloP100		-0.77
PromoterAI		0.037	Neutral

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: rs975021871; hg19: chr20-34287248;