6-31864579-CAAAAAAAA-CAAAAAA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_025257.3(SLC44A4):​c.2011+71_2011+72delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,231,340 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0083 (0 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: Uncertain_significance. The variant received 0 ACMG points.

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+72delTT		intron	N/A	NP_079533.2	A0A140VJH4
	SLC44A4	NM_001178044.2		c.1885+71_1885+72delTT		intron	N/A	NP_001171515.1	Q53GD3-4
	SLC44A4	NM_001178045.2		c.1783+71_1783+72delTT		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+72delTT		intron	N/A	ENSP00000229729.6	Q53GD3-1
	SLC44A4	ENST00000882851.1		c.2011+71_2011+72delTT		intron	N/A	ENSP00000552910.1
	SLC44A4	ENST00000882853.1		c.2011+71_2011+72delTT		intron	N/A	ENSP00000552912.1

Frequencies

GnomAD3 genomes AF: 0.0000541 AC: 7 AN: 129458 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000234

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000285

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000342

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00826 AC: 9105 AN: 1101844 Hom.: 0 AF XY: 0.00790 AC XY: 4413 AN XY: 558762

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

African (AFR) AF: 0.00778 AC: 195 AN: 25072

American (AMR) AF: 0.00796 AC: 285 AN: 35818

Ashkenazi Jewish (ASJ) AF: 0.00809 AC: 179 AN: 22138

East Asian (EAS) AF: 0.00195 AC: 72 AN: 36866

South Asian (SAS) AF: 0.00451 AC: 330 AN: 73210

European-Finnish (FIN) AF: 0.00394 AC: 180 AN: 45690

Middle Eastern (MID) AF: 0.00577 AC: 24 AN: 4160

European-Non Finnish (NFE) AF: 0.00928 AC: 7530 AN: 811220

Other (OTH) AF: 0.00650 AC: 310 AN: 47670

⚠️ 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: 0.0000541 AC: 7 AN: 129496 Hom.: 0 Cov.: 28 AF XY: 0.0000803 AC XY: 5 AN XY: 62296

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

African (AFR) AF: 0.00 AC: 0 AN: 36776

American (AMR) AF: 0.000233 AC: 3 AN: 12850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3066

East Asian (EAS) AF: 0.00 AC: 0 AN: 4492

South Asian (SAS) AF: 0.00 AC: 0 AN: 4118

European-Finnish (FIN) AF: 0.000285 AC: 2 AN: 7028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.0000342 AC: 2 AN: 58450

Other (OTH) AF: 0.00 AC: 0 AN: 1756

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000325184), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 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

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

Other links and lift over

dbSNP: rs5875335; hg19: chr6-31832356;