1-228175389-A-G

Variant names:

• chr1-228175389-A-G
• rs200319163
• NM_001010867.4:c.947A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001010867.4(IBA57):​c.947A>G​(p.Asn316Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N316T) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: IBA57 NM_001010867.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.40

Genes affected

IBA57 (HGNC:27302): (iron-sulfur cluster assembly factor IBA57) The protein encoded by this gene localizes to the mitochondrion and is part of the iron-sulfur cluster assembly pathway. The encoded protein functions late in the biosynthesis of mitochondrial 4Fe-4S proteins. Defects in this gene have been associated with autosomal recessive spastic paraplegia-74 and with multiple mitochondrial dysfunctions syndrome-3. Two transcript variants encoding different isoforms have been found for this gene. The smaller isoform is not likely to be localized to the mitochondrion since it lacks the amino-terminal transit peptide. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.078945786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IBA57	NM_001010867.4	c.947A>G	p.Asn316Ser	missense_variant	Exon 3 of 3	ENST00000366711.4	NP_001010867.1
IBA57	NM_001310327.2	c.368A>G	p.Asn123Ser	missense_variant	Exon 3 of 3		NP_001297256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IBA57	ENST00000366711.4	c.947A>G	p.Asn316Ser	missense_variant	Exon 3 of 3	2	NM_001010867.4	ENSP00000355672.3
IBA57	ENST00000484749.5	n.2947A>G		non_coding_transcript_exon_variant	Exon 3 of 3	5
IBA57	ENST00000546123.2	n.667A>G		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.7
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.23
Sift	Benign	0.61	T
Sift4G	Benign	0.68	T
Polyphen		0.16	B
Vest4		0.038
MutPred		0.52		Loss of sheet (P = 0.0315);
MVP		0.51
MPC		0.21
ClinPred		0.17	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.18
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200319163; hg19: chr1-228363090;