NM_205850.3:c.331A>C

Variant names:

• chr15-48134287-A-C
• rs1426654
• NM_205850.3:c.331A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_205850.3(SLC24A5):​c.331A>C​(p.Thr111Pro) 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 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. T111A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC24A5 NM_205850.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

Genes affected

SLC24A5 (HGNC:20611): (solute carrier family 24 member 5) This gene is a member of the potassium-dependent sodium/calcium exchanger family and encodes an intracellular membrane protein with 2 large hydrophilic loops and 2 sets of multiple transmembrane-spanning segments. Sequence variation in this gene has been associated with differences in skin pigmentation. [provided by RefSeq, Jul 2008]

SLC24A5 Gene-Disease associations (from GenCC):

• oculocutaneous albinism type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_205850.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.375359).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_205850.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC24A5	NM_205850.3	MANE Select	c.331A>C	p.Thr111Pro	missense	Exon 3 of 9	NP_995322.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC24A5	ENST00000341459.8	TSL:1 MANE Select	c.331A>C	p.Thr111Pro	missense	Exon 3 of 9	ENSP00000341550.3
	SLC24A5	ENST00000449382.2	TSL:1	c.151A>C	p.Thr51Pro	missense	Exon 2 of 8	ENSP00000389966.2
	SLC24A5	ENST00000463289.1	TSL:3	n.91A>C		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.17
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		7.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.0050	B
Vest4		0.28
MutPred		0.55		Loss of glycosylation at T111 (P = 0.0566)
MVP		0.74
MPC		0.091
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.75
gMVP		0.93
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs1426654; hg19: chr15-48426484;