1-1420592-C-G

Position:

• chr1-1420592-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001145210.3(ANKRD65):​c.210G>C​(p.Arg70Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANKRD65 NM_001145210.3 missense, splice_region
• Scores: Splicing: ADA: 0.9970
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.144

Genes affected

ANKRD65 (HGNC:42950): (ankyrin repeat domain 65)

ANKRD65-AS1 (HGNC:55844): (ANKRD65 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD65	NM_001145210.3	c.210G>C	p.Arg70Ser	missense_variant, splice_region_variant	3/4	ENST00000537107.6
ANKRD65-AS1	XR_946814.2	n.399+28C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD65	ENST00000537107.6	c.210G>C	p.Arg70Ser	missense_variant, splice_region_variant	3/4	5	NM_001145210.3	P1
ANKRD65-AS1	ENST00000428932.1	n.320+28C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Oct 29, 2021

The c.210G>C (p.R70S) alteration is located in exon 3 (coding exon 2) of the ANKRD65 gene. This alteration results from a G to C substitution at nucleotide position 210, causing the arginine (R) at amino acid position 70 to be replaced by a serine (S). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0022	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.75	T;.
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.17
Sift	Benign	0.039	D;.
Sift4G	Benign	0.15	T;T
Polyphen		0.89	P;P
Vest4		0.27
MutPred		0.33		Gain of phosphorylation at R70 (P = 0.0723);Gain of phosphorylation at R70 (P = 0.0723);
MVP		0.24
ClinPred		0.23	T
GERP RS		2.7
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		2.5
Varity_R		0.20
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-1355972;