1-205795339-G-A

Position:

• chr1-205795339-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_173854.6(SLC41A1):​c.1207+5C>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,614,180 control chromosomes in the GnomAD database, including 4 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: SLC41A1 NM_173854.6 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.00001818
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.11

Genes affected

SLC41A1 (HGNC:19429): (solute carrier family 41 member 1) Enables magnesium ion transmembrane transporter activity and magnesium:sodium antiporter activity. Involved in cellular magnesium ion homeostasis; cellular response to magnesium ion; and magnesium ion transmembrane transport. Located in basolateral plasma membrane. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC41A1	NM_173854.6	c.1207+5C>T		splice_donor_5th_base_variant, intron_variant		ENST00000367137.4
SLC41A1	XM_047416887.1	c.1207+5C>T		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC41A1	ENST00000367137.4	c.1207+5C>T		splice_donor_5th_base_variant, intron_variant		1	NM_173854.6	P1
SLC41A1	ENST00000468057.5	n.1003+5C>T		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant		2
SLC41A1	ENST00000484228.1	n.1273+5C>T		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000848 AC: 213 AN: 251218 Hom.: 0 AF XY: 0.000854 AC XY: 116 AN XY: 135784

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00185 AC: 2705 AN: 1461878 Hom.: 3 Cov.: 34 AF XY: 0.00174 AC XY: 1268 AN XY: 727240

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00224

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00103 AC: 157 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74476

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.00101

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00166

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2023

This sequence change falls in intron 9 of the SLC41A1 gene. It does not directly change the encoded amino acid sequence of the SLC41A1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200085602, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SLC41A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2058620). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.066
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0020
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: rs200085602; hg19: chr1-205764467;