rs76547866

Positions:

• chr15-48141109-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_205850.3(SLC24A5):​c.1079-4A>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,606,334 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (7 hom., cov: 32)
  • Exomes 𝑓: 0.015 (217 hom.)
• Consequence: SLC24A5 NM_205850.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001981
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.412

Genes affected

MYEF2 (HGNC:17940): (myelin expression factor 2) Enables RNA binding activity. Involved in myotube differentiation and neuron differentiation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 15-48141109-A-T is Benign according to our data. Variant chr15-48141109-A-T is described in ClinVar as [Benign]. Clinvar id is 263272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0085 (1294/152286) while in subpopulation NFE AF= 0.0149 (1015/68006). AF 95% confidence interval is 0.0142. There are 7 homozygotes in gnomad4. There are 608 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYEF2	NM_016132.5	c.*1799T>A		3_prime_UTR_variant	17/17	ENST00000324324.12
SLC24A5	NM_205850.3	c.1079-4A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000341459.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYEF2	ENST00000324324.12	c.*1799T>A		3_prime_UTR_variant	17/17	1	NM_016132.5	P4
SLC24A5	ENST00000341459.8	c.1079-4A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_205850.3	P1
SLC24A5	ENST00000449382.2	c.899-4A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
MYEF2	ENST00000558289.5	n.2839T>A		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.00852 AC: 1297 AN: 152168 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00282

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00763 AC: 1912 AN: 250702 Hom.: 14 AF XY: 0.00752 AC XY: 1019 AN XY: 135474

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.00487

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00465

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.00802

GnomAD4 exome AF: 0.0150 AC: 21821 AN: 1454048 Hom.: 217 Cov.: 28 AF XY: 0.0145 AC XY: 10516 AN XY: 723960

Gnomad4 AFR exome AF: 0.00262

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.00453

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00522

Gnomad4 FIN exome AF: 0.00268

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.00850 AC: 1294 AN: 152286 Hom.: 7 Cov.: 32 AF XY: 0.00816 AC XY: 608 AN XY: 74476

Gnomad4 AFR AF: 0.00281

Gnomad4 AMR AF: 0.00517

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.0149

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0125 Hom.: 6

Bravo AF: 0.00849

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0122

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	MYEF2: BS1, BS2; SLC24A5: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.1
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.018
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: rs76547866; hg19: chr15-48433306;