5-175510188-G-C

Position:

• chr5-175510188-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022754.7(SFXN1):​c.415G>C​(p.Asp139His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SFXN1 NM_022754.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.86

Genes affected

SFXN1 (HGNC:16085): (sideroflexin 1) Enables D-serine transmembrane transporter activity and L-serine transmembrane transporter activity. Involved in D-serine transport; L-serine transport; and serine import into mitochondrion. Located in mitochondrion. Is integral component of mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

SFXN1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFXN1	NM_022754.7	c.415G>C	p.Asp139His	missense_variant	4/11	ENST00000321442.10	NP_073591.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFXN1	ENST00000321442.10	c.415G>C	p.Asp139His	missense_variant	4/11	1	NM_022754.7	ENSP00000316905.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2023

The c.415G>C (p.D139H) alteration is located in exon 4 (coding exon 3) of the SFXN1 gene. This alteration results from a G to C substitution at nucleotide position 415, causing the aspartic acid (D) at amino acid position 139 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T;T;T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.2	.;M;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.8	D;D;.;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.012	D;D;.;D
Sift4G	Uncertain	0.021	D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D
Vest4		0.67, 0.72
MutPred		0.42		Gain of catalytic residue at D139 (P = 0.0763);Gain of catalytic residue at D139 (P = 0.0763);Gain of catalytic residue at D139 (P = 0.0763);Gain of catalytic residue at D139 (P = 0.0763);
MVP		0.42
MPC		0.85
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-174937191;