Genetic Variant SFXN4:c.937-146dupA (chr10-119141464-A-AT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_213649.2(SFXN4):c.937-146dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 324,518 control chromosomes in the GnomAD database, including 16 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0094 ( 15 hom., cov: 0)

Exomes 𝑓: 0.00090 ( 1 hom. )

Consequence

SFXN4
NM_213649.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0850

Publications

0 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

SFXN4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00939 (1364/145304) while in subpopulation AFR AF = 0.0327 (1266/38738). AF 95% confidence interval is 0.0312. There are 15 homozygotes in GnomAd4. There are 624 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213649.2. 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
	SFXN4	NM_213649.2	MANE Select	c.937-146dupA		intron	N/A	NP_998814.1	Q6P4A7-1
	SFXN4	NR_110305.1		n.1076-146dupA		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SFXN4	ENST00000355697.7	TSL:1 MANE Select	c.937-146_937-145insA	intron	N/A	ENSP00000347924.2	Q6P4A7-1
SFXN4	ENST00000955059.1		c.937-152_937-151insA	intron	N/A	ENSP00000625118.1
SFXN4	ENST00000461438.5	TSL:5	n.966-146_966-145insA	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00932

AC:

1353

AN:

145210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00515

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000213

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00649

Gnomad NFE

AF:

0.000179

Gnomad OTH

AF:

0.00499

GnomAD4 exome

AF:

0.000904

AC:

162

AN:

179214

Hom.:

AF XY:

0.000811

AC XY:

AN XY:

96162

show subpopulations

African (AFR)

AF:

0.0273

AC:

100

AN:

3660

American (AMR)

AF:

0.00184

AC:

AN:

4904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5188

East Asian (EAS)

AF:

0.00

AC:

AN:

11882

South Asian (SAS)

AF:

0.00

AC:

AN:

14570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15088

Middle Eastern (MID)

AF:

0.00261

AC:

AN:

766

European-Non Finnish (NFE)

AF:

0.000115

AC:

AN:

112910

Other (OTH)

AF:

0.00371

AC:

AN:

10246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00939

AC:

1364

AN:

145304

Hom.:

Cov.:

AF XY:

0.00888

AC XY:

624

AN XY:

70272

show subpopulations

African (AFR)

AF:

0.0327

AC:

1266

AN:

38738

American (AMR)

AF:

0.00514

AC:

AN:

14390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

4960

South Asian (SAS)

AF:

0.00

AC:

AN:

4694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8910

Middle Eastern (MID)

AF:

0.00694

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000179

AC:

AN:

66954

Other (OTH)

AF:

0.00494

AC:

AN:

2024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

126

189

252

315

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.085

Mutation Taster

=100/0

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

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10-119141464-ATTTTT-ATTTTTT

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