2-27212381-G-A

Variant names:

• chr2-27212381-G-A
• rs773247722
• NM_001170795.4:c.13G>A

Variant summary

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

The NM_001170795.4(ATRAID):​c.13G>A​(p.Asp5Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,398,264 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D5Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: ATRAID NM_001170795.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.229
• Publications: 1 publications found

Genes affected

ATRAID (HGNC:24090): (all-trans retinoic acid induced differentiation factor) This gene is thought to be involved in apoptosis, and may also be involved in hematopoietic development and differentiation. The use of alternative splice sites and promotors result in multiple transcript variants encoding different isoforms.[provided by RefSeq, Dec 2009]

SLC5A6 (HGNC:11041): (solute carrier family 5 member 6) Enables biotin transmembrane transporter activity and pantothenate transmembrane transporter activity. Involved in anion transmembrane transport and transport across blood-brain barrier. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC5A6 Gene-Disease associations (from GenCC):

• neurodegeneration, infantile-onset, biotin-responsive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• peripheral motor neuropathy, childhood-onset, biotin-responsive

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• inherited neurodegenerative disorder

  Inheritance: AR Classification: MODERATE Submitted by: Illumina

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=0.051898956).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170795.4. 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
	ATRAID	NM_001170795.4	MANE Select	c.13G>A	p.Asp5Asn	missense	Exon 1 of 7	NP_001164266.1	Q6UW56-1
	ATRAID	NM_016085.5		c.-302G>A		5_prime_UTR	Exon 1 of 7	NP_057169.2
	SLC5A6	NM_021095.4	MANE Select	c.-569C>T		upstream_gene	N/A	NP_066918.2	Q9Y289

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRAID	ENST00000380171.9	TSL:1 MANE Select	c.13G>A	p.Asp5Asn	missense	Exon 1 of 7	ENSP00000369518.4	Q6UW56-1
	ATRAID	ENST00000405489.7	TSL:1	c.-302G>A		5_prime_UTR	Exon 1 of 7	ENSP00000384033.3	Q6UW56-2
	ATRAID	ENST00000892973.1		c.13G>A	p.Asp5Asn	missense	Exon 1 of 7	ENSP00000563032.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000130 AC: 2 AN: 153838 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000358 AC: 5 AN: 1398264 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 689786

African (AFR) AF: 0.00 AC: 0 AN: 31540

American (AMR) AF: 0.00 AC: 0 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25138

East Asian (EAS) AF: 0.00 AC: 0 AN: 35826

South Asian (SAS) AF: 0.0000631 AC: 5 AN: 79198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078796

Other (OTH) AF: 0.00 AC: 0 AN: 57972

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000430 AC: 4

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.8
DANN	Benign	0.95
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.23
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.016
Sift	Benign	0.37	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.19		Loss of ubiquitination at K55 (P = 0.0247)
MVP		0.22
MPC		0.065
ClinPred		0.025	T
GERP RS		2.2
PromoterAI		-0.094	Neutral
Varity_R		0.037
gMVP		0.26
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs773247722; hg19: chr2-27435249;