5-140537517-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_017747.3(ANKHD1):c.7156C>G(p.Pro2386Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,613,472 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (6 hom.)
• Consequence: ANKHD1 NM_017747.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.91

Genes affected

ANKHD1 (HGNC:24714): (ankyrin repeat and KH domain containing 1) This gene encodes a protein with multiple ankyrin repeat domains and a single KH-domain. The protein is thought to function as a scaffolding protein, and it may be involved in the regulation of caspases and thereby play an antiapoptotic role in cell survival. Alternative splicing results in multiple transcript variants, one of which generates a fusion transcript (MASK-BP3) with the downstream eIF4E-binding protein 3 (EIF4EBP3) gene, resulting in a protein comprised of the ANKHD1 sequence for the majority of the protein and a different C-terminus due to an alternate reading frame for the EIF4EBP3 segments. [provided by RefSeq, Sep 2010]

ANKHD1-EIF4EBP3 (HGNC:):

SRA1 (HGNC:11281): (steroid receptor RNA activator 1) Both long non-coding and protein-coding RNAs are transcribed from this gene, and they represent alternatively spliced transcript variants. This gene was initially defined as a non-coding RNA, which is a coactivator for several nuclear receptors (NRs) and is associated with breast cancer. It has now been found that this gene is involved in the regulation of many NR and non-NR activities, including metabolism, adipogenesis and chromatin organization. The long non-coding RNA transcripts interact with a variety of proteins, including the protein encoded by this gene. The encoded protein acts as a transcriptional repressor by binding to the non-coding RNA. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANKHD1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0054234564).
• BP6: Variant 5-140537517-C-G is Benign according to our data. Variant chr5-140537517-C-G is described in ClinVar as [Benign]. Clinvar id is 775225.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 509 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKHD1	NM_017747.3	c.7156C>G	p.Pro2386Ala	missense_variant	31/34	ENST00000360839.7
ANKHD1-EIF4EBP3	NM_020690.6	c.7156C>G	p.Pro2386Ala	missense_variant	31/36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKHD1	ENST00000360839.7	c.7156C>G	p.Pro2386Ala	missense_variant	31/34	1	NM_017747.3	P1

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 509 AN: 152124 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000878 AC: 218 AN: 248292 Hom.: 2 AF XY: 0.000550 AC XY: 74 AN XY: 134434

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000360

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000410 AC: 599 AN: 1461230 Hom.: 6 Cov.: 30 AF XY: 0.000365 AC XY: 265 AN XY: 726974

Gnomad4 AFR exome AF: 0.0142

Gnomad4 AMR exome AF: 0.000516

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.00336 AC: 511 AN: 152242 Hom.: 2 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74446

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000349 Hom.: 0

Bravo AF: 0.00412

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D
MetaRNN	Benign	0.0054	T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	0.94	D;N;N;N
PrimateAI	Uncertain	0.49	T
REVEL	Benign	0.073
Sift4G	Benign	0.45	T;T;T;T;T;T
Polyphen		0.82	.;P;.;.;.;.
Vest4		0.53
MVP		0.21
MPC		0.49
ClinPred		0.037	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.21

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: rs139029039; hg19: chr5-139917102;