1-108817057-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152763.5(AKNAD1):c.2370A>G(p.Ile790Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.000012 (0 hom.)
• Consequence: AKNAD1 NM_152763.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.94

Genes affected

AKNAD1 (HGNC:28398): (AKNA domain containing 1) This gene encodes a protein which contains a domain found in an AT-hook-containing transcription factor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

LOC105378891 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01857698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKNAD1	NM_152763.5	c.2370A>G	p.Ile790Met	missense_variant	15/16	ENST00000370001.8
LOC105378891	XR_947687.3	n.53+3415T>C		intron_variant, non_coding_transcript_variant
AKNAD1	NR_049760.2	n.2500A>G		non_coding_transcript_exon_variant	13/14
LOC105378891	XR_007066280.1	n.53+3415T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKNAD1	ENST00000370001.8	c.2370A>G	p.Ile790Met	missense_variant	15/16	1	NM_152763.5	P2
AKNAD1	ENST00000466413.1	n.398A>G		non_coding_transcript_exon_variant	1/2	2
AKNAD1	ENST00000477908.1	n.155A>G		non_coding_transcript_exon_variant	2/3	3
AKNAD1	ENST00000474186.5	c.*119A>G		3_prime_UTR_variant, NMD_transcript_variant	13/14	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251248 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461718 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000302

ExAC AF: 0.0000247 AC: 3

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

Mar 23, 2022

The c.2370A>G (p.I790M) alteration is located in exon 15 (coding exon 14) of the AKNAD1 gene. This alteration results from a A to G substitution at nucleotide position 2370, causing the isoleucine (I) at amino acid position 790 to be replaced by a methionine (M). 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	0.059
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.15
Dann	Benign	0.25
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.019
Sift	Benign	0.42	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.067
MutPred		0.21		Loss of catalytic residue at L795 (P = 0.0447);
MVP		0.014
MPC		0.026
ClinPred		0.035	T
GERP RS		-11
Varity_R		0.051
gMVP		0.029

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs753254641; hg19: chr1-109359679;