17-50699882-C-A

Position:

• chr17-50699882-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052855.4(ANKRD40):​c.295G>T​(p.Asp99Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,354,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: ANKRD40 NM_052855.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0550

Genes affected

ANKRD40 (HGNC:28233): (ankyrin repeat domain 40)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07433194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD40	NM_052855.4	c.295G>T	p.Asp99Tyr	missense_variant	3/5	ENST00000285243.7	NP_443087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD40	ENST00000285243.7	c.295G>T	p.Asp99Tyr	missense_variant	3/5	1	NM_052855.4	ENSP00000285243.6
ANKRD40	ENST00000513072.1	c.61G>T	p.Asp21Tyr	missense_variant	2/2	2		ENSP00000468442.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1354512 Hom.: 0 Cov.: 31 AF XY: 0.00000151 AC XY: 1 AN XY: 661902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000351

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000847 AC: 1

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

Nov 29, 2023

The c.295G>T (p.D99Y) alteration is located in exon 3 (coding exon 3) of the ANKRD40 gene. This alteration results from a G to T substitution at nucleotide position 295, causing the aspartic acid (D) at amino acid position 99 to be replaced by a tyrosine (Y). 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	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.85	N;.
REVEL	Benign	0.052
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.45	T;T
Polyphen		0.11	B;.
Vest4		0.24
MutPred		0.33		Gain of phosphorylation at D99 (P = 0.0043);.;
MVP		0.19
MPC		0.38
ClinPred		0.28	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.14
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs772164531; hg19: chr17-48777243; COSMIC: COSV99035195; COSMIC: COSV99035195;