Genetic Variant ROMO1:c.-22C>T (chr20-35699435-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_080748.3(ROMO1):c.-22C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,184,152 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 19 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 14 hom. )

Consequence

ROMO1
NM_080748.3 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.585

Publications

1 publications found

Variant links:

Genes affected

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]

ROMO1 links:

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

NFS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 20-35699435-C-T is Benign according to our data. Variant chr20-35699435-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1316288.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 = 0.00835 (1272/152334) while in subpopulation AFR AF = 0.0289 (1201/41584). AF 95% confidence interval is 0.0275. There are 19 homozygotes in GnomAd4. There are 598 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080748.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ROMO1	NM_080748.3	MANE Select	c.-22C>T	5_prime_UTR	Exon 1 of 3	NP_542786.1	P60602-1
NFS1	NM_021100.5	MANE Select	c.-147G>A	upstream_gene	N/A	NP_066923.3
NFS1	NM_001198989.2		c.-147G>A	upstream_gene	N/A	NP_001185918.1	Q9Y697-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ROMO1	ENST00000374077.8	TSL:1 MANE Select	c.-22C>T	5_prime_UTR	Exon 1 of 3	ENSP00000363190.3	P60602-1
ROMO1	ENST00000374078.5	TSL:1	c.-17C>T	5_prime_UTR	Exon 1 of 3	ENSP00000363191.1	P60602-1
ROMO1	ENST00000938750.1		c.-110C>T	5_prime_UTR	Exon 1 of 3	ENSP00000608809.1

Frequencies

GnomAD3 genomes

AF:

0.00836

AC:

1273

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00860

GnomAD4 exome

AF:

0.000753

AC:

777

AN:

1031818

Hom.:

Cov.:

AF XY:

0.000684

AC XY:

349

AN XY:

510296

show subpopulations

African (AFR)

AF:

0.0284

AC:

637

AN:

22456

American (AMR)

AF:

0.00142

AC:

AN:

19664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17170

East Asian (EAS)

AF:

0.00

AC:

AN:

32162

South Asian (SAS)

AF:

0.0000167

AC:

AN:

59984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30906

Middle Eastern (MID)

AF:

0.000323

AC:

AN:

3092

European-Non Finnish (NFE)

AF:

0.0000474

AC:

AN:

801494

Other (OTH)

AF:

0.00160

AC:

AN:

44890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00835

AC:

1272

AN:

152334

Hom.:

Cov.:

AF XY:

0.00803

AC XY:

598

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0289

AC:

1201

AN:

41584

American (AMR)

AF:

0.00300

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68032

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

112

168

224

280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00363

Hom.:

Bravo

AF:

0.00998

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.58

PromoterAI

-0.0094

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=300/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over