6-31864579-CAAAAAAAA-CAAAAAAAAAA

Variant names:

• chr6-31864579-C-CAA
• rs5875335
• NM_025257.3:c.2011+71_2011+72dupTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_025257.3(SLC44A4):​c.2011+71_2011+72dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,251,968 control chromosomes in the GnomAD database, including 30 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0078 (26 hom., cov: 28)
  • Exomes 𝑓: 0.0059 (4 hom.)
• Consequence: SLC44A4 NM_025257.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.323
• Publications: 0 publications found

Genes affected

SLC44A4 (HGNC:13941): (solute carrier family 44 member 4) The protein encoded by this gene may be a sodium-dependent transmembrane transport protein involved in the uptake of choline by cholinergic neurons. Defects in this gene can cause sialidosis, a lysosomal storage disease. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

SLC44A4 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal dominant 72

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.075 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025257.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC44A4	NM_025257.3	MANE Select	c.2011+71_2011+72dupTT		intron	N/A	NP_079533.2	A0A140VJH4
	SLC44A4	NM_001178044.2		c.1885+71_1885+72dupTT		intron	N/A	NP_001171515.1	Q53GD3-4
	SLC44A4	NM_001178045.2		c.1783+71_1783+72dupTT		intron	N/A	NP_001171516.1	A0A1U9X8K7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC44A4	ENST00000229729.11	TSL:1 MANE Select	c.2011+71_2011+72dupTT		intron	N/A	ENSP00000229729.6	Q53GD3-1
	SLC44A4	ENST00000882851.1		c.2011+71_2011+72dupTT		intron	N/A	ENSP00000552910.1
	SLC44A4	ENST00000882853.1		c.2011+71_2011+72dupTT		intron	N/A	ENSP00000552912.1

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1015 AN: 129510 Hom.: 26 Cov.: 28

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.000326

Gnomad EAS AF: 0.00798

Gnomad SAS AF: 0.0822

Gnomad FIN AF: 0.000142

Gnomad MID AF: 0.00741

Gnomad NFE AF: 0.000821

Gnomad OTH AF: 0.00690

GnomAD4 exome AF: 0.00588 AC: 6601 AN: 1122418 Hom.: 4 Cov.: 0 AF XY: 0.00681 AC XY: 3876 AN XY: 568818

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0208 AC: 524 AN: 25222

American (AMR) AF: 0.00206 AC: 75 AN: 36460

Ashkenazi Jewish (ASJ) AF: 0.00234 AC: 53 AN: 22614

East Asian (EAS) AF: 0.00422 AC: 158 AN: 37464

South Asian (SAS) AF: 0.0397 AC: 2923 AN: 73624

European-Finnish (FIN) AF: 0.00109 AC: 51 AN: 46772

Middle Eastern (MID) AF: 0.00710 AC: 30 AN: 4226

European-Non Finnish (NFE) AF: 0.00295 AC: 2440 AN: 827490

Other (OTH) AF: 0.00715 AC: 347 AN: 48546

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00781 AC: 1012 AN: 129550 Hom.: 26 Cov.: 28 AF XY: 0.00884 AC XY: 551 AN XY: 62332

African (AFR) AF: 0.0140 AC: 515 AN: 36772

American (AMR) AF: 0.00459 AC: 59 AN: 12862

Ashkenazi Jewish (ASJ) AF: 0.000326 AC: 1 AN: 3068

East Asian (EAS) AF: 0.00824 AC: 37 AN: 4492

South Asian (SAS) AF: 0.0822 AC: 338 AN: 4110

European-Finnish (FIN) AF: 0.000142 AC: 1 AN: 7048

Middle Eastern (MID) AF: 0.00397 AC: 1 AN: 252

European-Non Finnish (NFE) AF: 0.000821 AC: 48 AN: 58480

Other (OTH) AF: 0.00683 AC: 12 AN: 1758

Alfa AF: 0.000232 Hom.: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5875335; hg19: chr6-31832356;