2-26764414-C-A

Variant names:

• chr2-26764414-C-A
• rs756337501
• NM_017877.4:c.65C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017877.4(SLC35F6):​c.65C>A​(p.Thr22Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000207 in 1,398,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: SLC35F6 NM_017877.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.09

Genes affected

SLC35F6 (HGNC:26055): (solute carrier family 35 member F6) Predicted to enable transmembrane transporter activity. Involved in negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway and positive regulation of cell population proliferation. Located in several cellular components, including lysosomal membrane; mitochondrion; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CENPA (HGNC:1851): (centromere protein A) Centromeres are the differentiated chromosomal domains that specify the mitotic behavior of chromosomes. This gene encodes a centromere protein which contains a histone H3 related histone fold domain that is required for targeting to the centromere. Centromere protein A is proposed to be a component of a modified nucleosome or nucleosome-like structure in which it replaces 1 or both copies of conventional histone H3 in the (H3-H4)2 tetrameric core of the nucleosome particle. The protein is a replication-independent histone that is a member of the histone H3 family. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC35F6	NM_017877.4	c.65C>A	p.Thr22Lys	missense_variant	Exon 1 of 6	ENST00000344420.10	NP_060347.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC35F6	ENST00000344420.10	c.65C>A	p.Thr22Lys	missense_variant	Exon 1 of 6	1	NM_017877.4	ENSP00000345528.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000207 AC: 29 AN: 1398648 Hom.: 0 Cov.: 31 AF XY: 0.0000246 AC XY: 17 AN XY: 689872

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000241

Gnomad4 OTH exome AF: 0.0000517

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65C>A (p.T22K) alteration is located in exon 1 (coding exon 1) of the SLC35F6 gene. This alteration results from a C to A substitution at nucleotide position 65, causing the threonine (T) at amino acid position 22 to be replaced by a lysine (K). 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	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.5	H
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.79		Gain of ubiquitination at T22 (P = 0.0238);
MVP		0.70
MPC		0.94
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.92
gMVP		0.96

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

LitVar

Other links and lift over

dbSNP: rs756337501; hg19: chr2-26987282;