NM_025257.3:c.559G>C

Variant names:

• chr6-31871532-C-G
• rs2242665
• NM_025257.3:c.559G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025257.3(SLC44A4):​c.559G>C​(p.Val187Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V187I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: SLC44A4 NM_025257.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.113
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05274594).

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.559G>C	p.Val187Leu	missense	Exon 8 of 21	NP_079533.2	A0A140VJH4
	SLC44A4	NM_001178044.2		c.433G>C	p.Val145Leu	missense	Exon 7 of 20	NP_001171515.1	Q53GD3-4
	SLC44A4	NM_001178045.2		c.331G>C	p.Val111Leu	missense	Exon 8 of 21	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.559G>C	p.Val187Leu	missense	Exon 8 of 21	ENSP00000229729.6	Q53GD3-1
	SLC44A4	ENST00000414427.1	TSL:5	c.544G>C	p.Val182Leu	missense	Exon 8 of 13	ENSP00000398901.1	H0Y5I3
	SLC44A4	ENST00000882851.1		c.559G>C	p.Val187Leu	missense	Exon 8 of 21	ENSP00000552910.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 57

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.50
DANN	Benign	0.88
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.47	N
PhyloP100		-0.11
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.0050
Sift	Benign	0.34	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.052
MutPred		0.32		Gain of glycosylation at P189 (P = 0.1064)
MVP		0.030
MPC		0.21
ClinPred		0.069	T
GERP RS		0.52
Varity_R		0.027
gMVP		0.50
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2242665; hg19: chr6-31839309;