4-124669177-T-C

Variant names:

• chr4-124669177-T-C
• rs1476477094
• NM_020337.3:c.4100A>G

Variant summary

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

The NM_020337.3(ANKRD50):​c.4100A>G​(p.Tyr1367Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,514 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ANKRD50 NM_020337.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30

Genes affected

ANKRD50 (HGNC:29223): (ankyrin repeat domain containing 50) Involved in endocytic recycling. Predicted to be located in endosome. [provided by Alliance of Genome Resources, Apr 2022]

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 rank	MANE	Protein	UniProt
ANKRD50	NM_020337.3	c.4100A>G	p.Tyr1367Cys	missense_variant	Exon 4 of 5	ENST00000504087.6	NP_065070.1
ANKRD50	NM_001167882.2	c.3563A>G	p.Tyr1188Cys	missense_variant	Exon 3 of 4		NP_001161354.1
ANKRD50	XM_017008471.2	c.4100A>G	p.Tyr1367Cys	missense_variant	Exon 3 of 4		XP_016863960.1
ANKRD50	XM_047415992.1	c.4100A>G	p.Tyr1367Cys	missense_variant	Exon 4 of 5		XP_047271948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD50	ENST00000504087.6	c.4100A>G	p.Tyr1367Cys	missense_variant	Exon 4 of 5	2	NM_020337.3	ENSP00000425658.1
ANKRD50	ENST00000515641.1	c.3563A>G	p.Tyr1188Cys	missense_variant	Exon 3 of 4	2		ENSP00000425355.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251054 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135686

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461514 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727058

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4100A>G (p.Y1367C) alteration is located in exon 4 (coding exon 3) of the ANKRD50 gene. This alteration results from a A to G substitution at nucleotide position 4100, causing the tyrosine (Y) at amino acid position 1367 to be replaced by a cysteine (C). 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	0.13
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.012
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.90	L;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.082	T;T
Polyphen		0.061	B;.
Vest4		0.89
MutPred		0.39		Gain of glycosylation at Y1367 (P = 0.0308);.;
MVP		0.66
MPC		0.67
ClinPred		0.81	D
GERP RS		4.1
Varity_R		0.31
gMVP		0.36

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: rs1476477094; hg19: chr4-125590332;