1-1419437-A-G

Variant names:

• chr1-1419437-A-G
• rs1237088296
• NM_001145210.3:c.863T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001145210.3(ANKRD65):​c.863T>C​(p.Leu288Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,397,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANKRD65 NM_001145210.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145210.3. 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
	ANKRD65	NM_001145210.3	MANE Select	c.863T>C	p.Leu288Pro	missense	Exon 4 of 4	NP_001138682.1	E5RJM6-1
	ANKRD65	NM_001243535.2		c.322T>C	p.Trp108Arg	missense	Exon 3 of 3	NP_001230464.1	E5RJM6-2
	ANKRD65	NM_001375659.1		c.322T>C	p.Trp108Arg	missense	Exon 2 of 2	NP_001362588.1	E5RJM6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD65	ENST00000537107.6	TSL:5 MANE Select	c.863T>C	p.Leu288Pro	missense	Exon 4 of 4	ENSP00000445688.1	E5RJM6-1
	ANKRD65	ENST00000427211.3	TSL:1	c.322T>C	p.Trp108Arg	missense	Exon 3 of 3	ENSP00000428419.1	E5RJM6-2
	ANKRD65	ENST00000520296.5	TSL:1	c.*105T>C		3_prime_UTR	Exon 3 of 3	ENSP00000429035.1	E5RJM6-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000667 AC: 1 AN: 149844 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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397118 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689146

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25162

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.00 AC: 0 AN: 79218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078822

Other (OTH) AF: 0.00 AC: 0 AN: 57968

GnomAD4 genome Cov.: 33

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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.046	D
PhyloP100		2.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.053	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.90		Loss of stability (P = 0.0176)
MVP		0.29
ClinPred		0.79	D
GERP RS		3.4
Varity_R		0.87
gMVP		0.79
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: rs1237088296; hg19: chr1-1354817;