NM_213649.2:c.538-199T>C

Variant names:

• chr10-119156955-A-G
• rs2297696
• NM_213649.2:c.538-199T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_213649.2(SFXN4):​c.538-199T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 151,840 control chromosomes in the GnomAD database, including 7,562 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.30 (7562 hom., cov: 31)
• Consequence: SFXN4 NM_213649.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.347
• Publications: 13 publications found

Genes affected

SFXN4 (HGNC:16088): (sideroflexin 4) This gene encodes a member of the sideroflexin family. The encoded protein is a transmembrane protein of the inner mitochondrial membrane, and is required for mitochondrial respiratory homeostasis and erythropoiesis. Mutations in this gene are associated with mitochondriopathy and macrocytic anemia. Alternatively spliced transcript variants have been found in this gene. [provided by RefSeq, Jan 2014]

SFXN4 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-119156955-A-G is Benign according to our data. Variant chr10-119156955-A-G is described in ClinVar as Benign. ClinVar VariationId is 667486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFXN4	NM_213649.2	c.538-199T>C		intron_variant	Intron 9 of 13	ENST00000355697.7	NP_998814.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFXN4	ENST00000355697.7	c.538-199T>C		intron_variant	Intron 9 of 13	1	NM_213649.2	ENSP00000347924.2

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45406 AN: 151722 Hom.: 7566 Cov.: 31

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.308

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.299 AC: 45401 AN: 151840 Hom.: 7562 Cov.: 31 AF XY: 0.304 AC XY: 22547 AN XY: 74154

African (AFR) AF: 0.163 AC: 6754 AN: 41414

American (AMR) AF: 0.285 AC: 4345 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1055 AN: 3468

East Asian (EAS) AF: 0.169 AC: 877 AN: 5178

South Asian (SAS) AF: 0.390 AC: 1879 AN: 4816

European-Finnish (FIN) AF: 0.458 AC: 4808 AN: 10492

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24590 AN: 67938

Other (OTH) AF: 0.309 AC: 652 AN: 2110

Alfa AF: 0.336 Hom.: 37813

Bravo AF: 0.274

Asia WGS AF: 0.304 AC: 1055 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.9
DANN	Benign	0.50
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

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: rs2297696; hg19: chr10-120916467;