9-105348387-C-T

Variant names:

• chr9-105348387-C-T
• rs74511615
• NM_080546.5:c.436C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_080546.5(SLC44A1):​c.436C>T​(p.Pro146Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,611,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: SLC44A1 NM_080546.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62
• Publications: 2 publications found

Genes affected

SLC44A1 (HGNC:18798): (solute carrier family 44 member 1) Enables choline transmembrane transporter activity. Involved in choline transport and transmembrane transport. Located in several cellular components, including cytosol; mitochondrion; and nucleoplasm. Implicated in high grade glioma. [provided by Alliance of Genome Resources, Apr 2022]

SLC44A1 Gene-Disease associations (from GenCC):

• neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.026419401).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080546.5. 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
	SLC44A1	NM_080546.5	MANE Select	c.436C>T	p.Pro146Ser	missense	Exon 5 of 16	NP_536856.2
	SLC44A1	NM_001330731.2		c.436C>T	p.Pro146Ser	missense	Exon 5 of 16	NP_001317660.1	Q8WWI5-2
	SLC44A1	NM_001286730.2		c.436C>T	p.Pro146Ser	missense	Exon 5 of 16	NP_001273659.1	Q8WWI5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC44A1	ENST00000374720.8	TSL:1 MANE Select	c.436C>T	p.Pro146Ser	missense	Exon 5 of 16	ENSP00000363852.3	Q8WWI5-1
	SLC44A1	ENST00000374723.5	TSL:1	c.436C>T	p.Pro146Ser	missense	Exon 5 of 16	ENSP00000363855.1	Q8WWI5-3
	SLC44A1	ENST00000470972.5	TSL:1	n.436C>T		non_coding_transcript_exon	Exon 5 of 17	ENSP00000433072.1	Q8WWI5-1

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000490 AC: 123 AN: 251116 AF XY: 0.000464

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000810

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000443 AC: 646 AN: 1458864 Hom.: 0 Cov.: 28 AF XY: 0.000446 AC XY: 324 AN XY: 725884

African (AFR) AF: 0.000120 AC: 4 AN: 33394

American (AMR) AF: 0.000515 AC: 23 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 86112

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53404

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.000490 AC: 544 AN: 1109622

Other (OTH) AF: 0.000349 AC: 21 AN: 60252

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74400

African (AFR) AF: 0.000120 AC: 5 AN: 41550

American (AMR) AF: 0.000327 AC: 5 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000648 AC: 44 AN: 67946

Other (OTH) AF: 0.00143 AC: 3 AN: 2102

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.000450

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.000656

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.29
Sift	Benign	0.80	T
Sift4G	Benign	0.49	T
Polyphen		0.0040	B
Vest4		0.21
MVP		0.64
MPC		0.33
ClinPred		0.022	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.81
Mutation Taster		=67/33	polymorphism

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: rs74511615; hg19: chr9-108110668;