1-108834468-C-G

Variant names:

• chr1-108834468-C-G
• rs146520059
• NM_152763.5:c.1725G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152763.5(AKNAD1):​c.1725G>C​(p.Met575Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000683 in 1,610,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: AKNAD1 NM_152763.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.83
• Publications: 0 publications found

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]

ENSG00000307428 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045936346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKNAD1	NM_152763.5	c.1725G>C	p.Met575Ile	missense_variant	Exon 9 of 16	ENST00000370001.8	NP_689976.2
AKNAD1	NR_049760.2	n.1958+3082G>C		intron_variant	Intron 8 of 13
LOC105378891	XR_007066273.1	n.294+132C>G		intron_variant	Intron 3 of 4
LOC105378891	XR_947687.3	n.269+132C>G		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKNAD1	ENST00000370001.8	c.1725G>C	p.Met575Ile	missense_variant	Exon 9 of 16	1	NM_152763.5	ENSP00000359018.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151948 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000811 AC: 2 AN: 246720 AF XY: 0.0000150

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459004 Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7 AN XY: 725422

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 85488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1110850

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151948 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74212

African (AFR) AF: 0.00 AC: 0 AN: 41352

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1725G>C (p.M575I) alteration is located in exon 9 (coding exon 8) of the AKNAD1 gene. This alteration results from a G to C substitution at nucleotide position 1725, causing the methionine (M) at amino acid position 575 to be replaced by an isoleucine (I). 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	0.18
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.015
DANN	Benign	0.61
DEOGEN2	Benign	0.0012	T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.39	T;T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;.;N
PhyloP100		-1.8
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.040	N;N;N
REVEL	Benign	0.078
Sift	Benign	0.94	T;T;T
Sift4G	Benign	0.45	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.067
MutPred		0.22		Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);
MVP		0.014
MPC		0.027
ClinPred		0.041	T
GERP RS		-4.3
Varity_R		0.038
gMVP		0.076
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs146520059; hg19: chr1-109377090;