Genetic Variant SLC44A4:c.2011+70_2011+72dupTTT (chr6-31864579-C-CAAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_025257.3(SLC44A4):c.2011+70_2011+72dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,259,264 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

SLC44A4
NM_025257.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.323

Publications

0 publications found

Variant links:

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

SLC44A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 20 AD gene.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC44A4	NM_025257.3	MANE Select	c.2011+70_2011+72dupTTT	intron	N/A	NP_079533.2	A0A140VJH4
SLC44A4	NM_001178044.2		c.1885+70_1885+72dupTTT	intron	N/A	NP_001171515.1	Q53GD3-4
SLC44A4	NM_001178045.2		c.1783+70_1783+72dupTTT	intron	N/A	NP_001171516.1	A0A1U9X8K7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC44A4	ENST00000229729.11	TSL:1 MANE Select	c.2011+70_2011+72dupTTT	intron	N/A	ENSP00000229729.6	Q53GD3-1
SLC44A4	ENST00000882851.1		c.2011+70_2011+72dupTTT	intron	N/A	ENSP00000552910.1
SLC44A4	ENST00000882853.1		c.2011+70_2011+72dupTTT	intron	N/A	ENSP00000552912.1

Frequencies

GnomAD3 genomes

AF:

0.000154

AC:

AN:

129538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000490

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000483

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000237

AC:

268

AN:

1129686

Hom.:

Cov.:

AF XY:

0.000306

AC XY:

175

AN XY:

572578

show subpopulations

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

African (AFR)

AF:

0.000472

AC:

AN:

25408

American (AMR)

AF:

0.00

AC:

AN:

36556

Ashkenazi Jewish (ASJ)

AF:

0.000132

AC:

AN:

22686

East Asian (EAS)

AF:

0.000240

AC:

AN:

37578

South Asian (SAS)

AF:

0.00193

AC:

144

AN:

74664

European-Finnish (FIN)

AF:

0.0000854

AC:

AN:

46856

Middle Eastern (MID)

AF:

0.000236

AC:

AN:

4244

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

832878

Other (OTH)

AF:

0.000184

AC:

AN:

48816

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.283

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000154

AC:

AN:

129578

Hom.:

Cov.:

AF XY:

0.000241

AC XY:

AN XY:

62348

show subpopulations

African (AFR)

AF:

0.000489

AC:

AN:

36786

American (AMR)

AF:

0.00

AC:

AN:

12862

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3070

East Asian (EAS)

AF:

0.00

AC:

AN:

4492

South Asian (SAS)

AF:

0.000486

AC:

AN:

4118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

58484

Other (OTH)

AF:

0.00

AC:

AN:

1756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.32

Splicing

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

Publications

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6-31864579-CAAAAAAAA-CAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over