3-15677010-C-T

Variant names:

• chr3-15677010-C-T
• rs2067005440
• NM_001349278.2:c.2837G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001349278.2(ANKRD28):​c.2837G>A​(p.Arg946Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,210 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R946G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ANKRD28 NM_001349278.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.22
• Publications: 0 publications found

Genes affected

ANKRD28 (HGNC:29024): (ankyrin repeat domain 28) Predicted to be located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

BTD (HGNC:1122): (biotinidase) The protein encoded by this gene functions to recycle protein-bound biotin by cleaving biocytin (biotin-epsilon-lysine), a normal product of carboxylase degradation, resulting in regeneration of free biotin. The encoded protein has also been shown to have biotinyl transferase activity. Mutations in this gene are associated with biotinidase deficiency. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Aug 2013]

BTD Gene-Disease associations (from GenCC):

• biotinidase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19214961).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349278.2. 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
	ANKRD28	NM_001349278.2	MANE Select	c.2837G>A	p.Arg946Lys	missense	Exon 26 of 28	NP_001336207.1	O15084-4
	ANKRD28	NM_001349277.2		c.2846G>A	p.Arg949Lys	missense	Exon 26 of 28	NP_001336206.1	O15084-1
	ANKRD28	NM_015199.4		c.2747G>A	p.Arg916Lys	missense	Exon 26 of 28	NP_056014.2	O15084-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD28	ENST00000683139.1	MANE Select	c.2837G>A	p.Arg946Lys	missense	Exon 26 of 28	ENSP00000508086.1	O15084-4
	ANKRD28	ENST00000399451.6	TSL:1	c.2747G>A	p.Arg916Lys	missense	Exon 26 of 28	ENSP00000382379.2	O15084-3
	ANKRD28	ENST00000624145.3	TSL:2	c.2285G>A	p.Arg762Lys	missense	Exon 26 of 28	ENSP00000485421.1	O15084-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461210 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726890

African (AFR) AF: 0.000149 AC: 5 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111596

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.097
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.050	N
PhyloP100		3.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.13
Sift	Benign	0.91	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.32
MutPred		0.50		Gain of ubiquitination at R916 (P = 0.0185)
MVP		0.30
MPC		0.18
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.20
gMVP		0.56
Mutation Taster		=80/20	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: rs2067005440; hg19: chr3-15718517;