chr6-31874723-T-C

Variant names:

• chr6-31874723-T-C
• rs1135402753
• NM_025257.3:c.466A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025257.3(SLC44A4):​c.466A>G​(p.Met156Val) variant causes a missense, splice region 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. 17/26 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as no classifications from unflagged records (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC44A4 NM_025257.3 missense, splice_region
• Scores: Splicing: ADA: 0.1523
• Clinical Significance: no classifications from unflagged records no classifications from unflagged records P:1
• Conservation: PhyloP100: 0.652
• Publications: 1 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12831709).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC44A4	NM_025257.3	MANE Select	c.466A>G	p.Met156Val	missense splice_region	Exon 6 of 21	NP_079533.2
	SLC44A4	NM_001178045.2		c.238A>G	p.Met80Val	missense splice_region	Exon 6 of 21	NP_001171516.1
	SLC44A4	NM_001178044.2		c.343-203A>G		intron	N/A	NP_001171515.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC44A4	ENST00000229729.11	TSL:1 MANE Select	c.466A>G	p.Met156Val	missense splice_region	Exon 6 of 21	ENSP00000229729.6
	SLC44A4	ENST00000414427.1	TSL:5	c.451A>G	p.Met151Val	missense splice_region	Exon 6 of 13	ENSP00000398901.1
	SLC44A4	ENST00000544672.5	TSL:2	c.238A>G	p.Met80Val	missense splice_region	Exon 6 of 21	ENSP00000444109.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1

Revision: no classifications from unflagged records

Submissions by phenotype

Hearing loss, autosomal dominant 72 Pathogenic:1

Sep 19, 2018

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.0092	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.65
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.084
Sift	Benign	0.10	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.48		Gain of sheet (P = 0.0827)
MVP		0.29
MPC		0.23
ClinPred		0.073	T
GERP RS		2.4
Varity_R		0.16
gMVP		0.66
Mutation Taster		=93/7	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.15
dbscSNV1_RF	Benign	0.27
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: -2

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

Other links and lift over

dbSNP: rs1135402753; hg19: chr6-31842500;