3-15677540-A-C

Variant names:

• chr3-15677540-A-C
• rs759882787
• NM_001349278.2:c.2730T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001349278.2(ANKRD28):​c.2730T>G​(p.Ser910Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,612,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ANKRD28 NM_001349278.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.067845196).
• BS2: High AC in GnomAdExome4 at 28 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.2730T>G	p.Ser910Arg	missense	Exon 25 of 28	NP_001336207.1	O15084-4
	ANKRD28	NM_001349277.2		c.2739T>G	p.Ser913Arg	missense	Exon 25 of 28	NP_001336206.1	O15084-1
	ANKRD28	NM_015199.4		c.2640T>G	p.Ser880Arg	missense	Exon 25 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.2730T>G	p.Ser910Arg	missense	Exon 25 of 28	ENSP00000508086.1	O15084-4
	ANKRD28	ENST00000399451.6	TSL:1	c.2640T>G	p.Ser880Arg	missense	Exon 25 of 28	ENSP00000382379.2	O15084-3
	ANKRD28	ENST00000624145.3	TSL:2	c.2178T>G	p.Ser726Arg	missense	Exon 25 of 28	ENSP00000485421.1	O15084-2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000442 AC: 11 AN: 248778 AF XY: 0.0000519

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000613

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1460502 Hom.: 0 Cov.: 29 AF XY: 0.0000179 AC XY: 13 AN XY: 726554

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.000631 AC: 25 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111110

Other (OTH) AF: 0.0000497 AC: 3 AN: 60312

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000579 AC: 7

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	-0.38	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.73	N
PhyloP100		2.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.14
Sift	Benign	0.031	D
Sift4G	Uncertain	0.027	D
Polyphen		0.0	B
Vest4		0.24
MutPred		0.54		Loss of disorder (P = 0.0822)
MVP		0.41
MPC		0.20
ClinPred		0.11	T
GERP RS		5.3
Varity_R		0.18
gMVP		0.10
Mutation Taster		=78/22	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: rs759882787; hg19: chr3-15719047; COSMIC: COSV67520505; COSMIC: COSV67520505;