19-32599733-G-C

Position:

• chr19-32599733-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032139.3(ANKRD27):​c.2890C>G​(p.Pro964Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANKRD27 NM_032139.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50

Genes affected

ANKRD27 (HGNC:25310): (ankyrin repeat domain 27) Enables guanyl-nucleotide exchange factor activity and small GTPase binding activity. Involved in endocytic recycling and negative regulation of SNARE complex assembly. Acts upstream of or within early endosome to late endosome transport. Located in endosome; lysosome; and plasma membrane. Implicated in eosinophilic esophagitis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30376258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD27	NM_032139.3	c.2890C>G	p.Pro964Ala	missense_variant	28/29	ENST00000306065.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD27	ENST00000306065.9	c.2890C>G	p.Pro964Ala	missense_variant	28/29	1	NM_032139.3	P1
ANKRD27	ENST00000587667.1	n.359C>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461004 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726732

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2022

The c.2890C>G (p.P964A) alteration is located in exon 28 (coding exon 27) of the ANKRD27 gene. This alteration results from a C to G substitution at nucleotide position 2890, causing the proline (P) at amino acid position 964 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.14
Sift	Uncertain	0.028	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.91	P
Vest4		0.42
MVP		0.79
MPC		0.28
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.10
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1330142821; hg19: chr19-33090639;