6-167896967-A-G

Position:

• chr6-167896967-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001386888.1(AFDN):​c.1312A>G​(p.Ile438Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,600,696 control chromosomes in the GnomAD database, including 580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (27 hom., cov: 33)
  • Exomes 𝑓: 0.025 (553 hom.)
• Consequence: AFDN NM_001386888.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.95

Genes affected

AFDN (HGNC:7137): (afadin, adherens junction formation factor) This gene encodes a multi-domain protein involved in signaling and organization of cell junctions during embryogenesis. It has also been identified as the fusion partner of acute lymphoblastic leukemia (ALL-1) gene, involved in acute myeloid leukemias with t(6;11)(q27;q23) translocation. Alternatively spliced transcript variants encoding different isoforms have been described for this gene, however, not all have been fully characterized.[provided by RefSeq, May 2011]

AFDN (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008843809).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0177 (2698/152346) while in subpopulation NFE AF= 0.026 (1767/68034). AF 95% confidence interval is 0.025. There are 27 homozygotes in gnomad4. There are 1295 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 2698 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFDN	NM_001386888.1	c.1312A>G	p.Ile438Val	missense_variant	10/34	ENST00000683244.1	NP_001373817.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFDN	ENST00000683244.1	c.1312A>G	p.Ile438Val	missense_variant	10/34		NM_001386888.1	ENSP00000507324.1

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2697 AN: 152226 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.00458

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0239

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0260

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0186 AC: 4672 AN: 250868 Hom.: 61 AF XY: 0.0194 AC XY: 2628 AN XY: 135600

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0138

Gnomad FIN exome AF: 0.0258

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0252

GnomAD4 exome AF: 0.0247 AC: 35825 AN: 1448350 Hom.: 553 Cov.: 26 AF XY: 0.0246 AC XY: 17752 AN XY: 721440

Gnomad4 AFR exome AF: 0.00382

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.0250

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0142

Gnomad4 FIN exome AF: 0.0261

Gnomad4 NFE exome AF: 0.0274

Gnomad4 OTH exome AF: 0.0258

GnomAD4 genome AF: 0.0177 AC: 2698 AN: 152346 Hom.: 27 Cov.: 33 AF XY: 0.0174 AC XY: 1295 AN XY: 74494

Gnomad4 AFR AF: 0.00459

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.0239

Gnomad4 NFE AF: 0.0260

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0241 Hom.: 88

Bravo AF: 0.0165

TwinsUK AF: 0.0353 AC: 131

ALSPAC AF: 0.0288 AC: 111

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.0263 AC: 226

ExAC AF: 0.0178 AC: 2159

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0247

EpiControl AF: 0.0258

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Mar 25, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;.;.;T;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
MetaRNN	Benign	0.0088	T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.8	.;.;M;.;M;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.63	N;N;N;N;N;N;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0050	D;D;D;D;D;D;.
Sift4G	Benign	0.19	T;T;T;T;T;T;T
Polyphen		0.34, 0.96	.;.;B;.;.;D;.
Vest4		0.51
MPC		0.99
ClinPred		0.052	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
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: rs35140809; hg19: chr6-168297647; COSMIC: COSV99053086;