chr6-31864579-CA-C

Variant names:

• chr6-31864579-CA-C
• rs5875335
• NM_025257.3:c.2011+72delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_025257.3(SLC44A4):​c.2011+72delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0769 in 129,280 control chromosomes in the GnomAD database, including 432 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.077 (432 hom., cov: 28)
  • Exomes 𝑓: 0.27 (105 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC44A4 NM_025257.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 6-31864579-CA-C is Benign according to our data. Variant chr6-31864579-CA-C is described in ClinVar as Benign. ClinVar VariationId is 1243584.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 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+72delT		intron	N/A	NP_079533.2	A0A140VJH4
	SLC44A4	NM_001178044.2		c.1885+72delT		intron	N/A	NP_001171515.1	Q53GD3-4
	SLC44A4	NM_001178045.2		c.1783+72delT		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+72delT		intron	N/A	ENSP00000229729.6	Q53GD3-1
	SLC44A4	ENST00000882851.1		c.2011+72delT		intron	N/A	ENSP00000552910.1
	SLC44A4	ENST00000882853.1		c.2011+72delT		intron	N/A	ENSP00000552912.1

Frequencies

GnomAD3 genomes AF: 0.0767 AC: 9916 AN: 129240 Hom.: 431 Cov.: 28

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.0353

Gnomad AMR AF: 0.0805

Gnomad ASJ AF: 0.0525

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.00169

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.0556

Gnomad NFE AF: 0.0581

Gnomad OTH AF: 0.0768

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.273 AC: 273835 AN: 1001986 Hom.: 105 Cov.: 0 AF XY: 0.274 AC XY: 138740 AN XY: 506582

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

African (AFR) AF: 0.227 AC: 5368 AN: 23676

American (AMR) AF: 0.318 AC: 10063 AN: 31642

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 5602 AN: 19000

East Asian (EAS) AF: 0.299 AC: 8387 AN: 28072

South Asian (SAS) AF: 0.215 AC: 14344 AN: 66750

European-Finnish (FIN) AF: 0.290 AC: 10984 AN: 37852

Middle Eastern (MID) AF: 0.221 AC: 832 AN: 3770

European-Non Finnish (NFE) AF: 0.276 AC: 206501 AN: 748970

Other (OTH) AF: 0.278 AC: 11754 AN: 42254

⚠️ 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: 0.0769 AC: 9940 AN: 129280 Hom.: 432 Cov.: 28 AF XY: 0.0738 AC XY: 4591 AN XY: 62184

African (AFR) AF: 0.137 AC: 5028 AN: 36760

American (AMR) AF: 0.0807 AC: 1036 AN: 12844

Ashkenazi Jewish (ASJ) AF: 0.0525 AC: 161 AN: 3066

East Asian (EAS) AF: 0.00156 AC: 7 AN: 4488

South Asian (SAS) AF: 0.00146 AC: 6 AN: 4116

European-Finnish (FIN) AF: 0.0191 AC: 133 AN: 6974

Middle Eastern (MID) AF: 0.0595 AC: 15 AN: 252

European-Non Finnish (NFE) AF: 0.0581 AC: 3388 AN: 58322

Other (OTH) AF: 0.0806 AC: 141 AN: 1750

Alfa AF: 0.00371 Hom.: 3

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

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; COSMIC: COSV57666430; COSMIC: COSV57666430;