chr6-31864579-C-CA

Variant names:

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

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+72dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,216,504 control chromosomes in the GnomAD database, including 1,319 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1273 hom., cov: 28)
  • Exomes 𝑓: 0.12 (46 hom.)
• 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-C-CA is Benign according to our data. Variant chr6-31864579-C-CA is described in ClinVar as Benign. ClinVar VariationId is 1269949.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.249 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+72dupT		intron	N/A	NP_079533.2	A0A140VJH4
	SLC44A4	NM_001178044.2		c.1885+72dupT		intron	N/A	NP_001171515.1	Q53GD3-4
	SLC44A4	NM_001178045.2		c.1783+72dupT		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+72dupT		intron	N/A	ENSP00000229729.6	Q53GD3-1
	SLC44A4	ENST00000882851.1		c.2011+72dupT		intron	N/A	ENSP00000552910.1
	SLC44A4	ENST00000882853.1		c.2011+72dupT		intron	N/A	ENSP00000552912.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 14386 AN: 129370 Hom.: 1271 Cov.: 28

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.00565

Gnomad AMR AF: 0.0902

Gnomad ASJ AF: 0.0508

Gnomad EAS AF: 0.0723

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.0449

Gnomad OTH AF: 0.122

GnomAD4 exome AF: 0.123 AC: 134022 AN: 1087096 Hom.: 46 Cov.: 0 AF XY: 0.124 AC XY: 68072 AN XY: 550588

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

African (AFR) AF: 0.234 AC: 5767 AN: 24680

American (AMR) AF: 0.0856 AC: 3022 AN: 35284

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2318 AN: 21502

East Asian (EAS) AF: 0.0984 AC: 3422 AN: 34768

South Asian (SAS) AF: 0.157 AC: 11361 AN: 72196

European-Finnish (FIN) AF: 0.0760 AC: 3369 AN: 44306

Middle Eastern (MID) AF: 0.139 AC: 564 AN: 4068

European-Non Finnish (NFE) AF: 0.122 AC: 98395 AN: 803592

Other (OTH) AF: 0.124 AC: 5804 AN: 46700

⚠️ 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: 0.111 AC: 14397 AN: 129408 Hom.: 1273 Cov.: 28 AF XY: 0.111 AC XY: 6933 AN XY: 62252

African (AFR) AF: 0.253 AC: 9307 AN: 36732

American (AMR) AF: 0.0901 AC: 1158 AN: 12848

Ashkenazi Jewish (ASJ) AF: 0.0508 AC: 156 AN: 3068

East Asian (EAS) AF: 0.0721 AC: 323 AN: 4480

South Asian (SAS) AF: 0.115 AC: 474 AN: 4118

European-Finnish (FIN) AF: 0.0162 AC: 114 AN: 7022

Middle Eastern (MID) AF: 0.111 AC: 28 AN: 252

European-Non Finnish (NFE) AF: 0.0449 AC: 2621 AN: 58426

Other (OTH) AF: 0.121 AC: 212 AN: 1754

Alfa AF: 0.00642 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)		0.040		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;