1-108827229-C-T

Variant names:

• chr1-108827229-C-T
• rs775377275
• NM_152763.5:c.1912G>A

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.1912G>A​(p.Ala638Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,222 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: 0.0000021 (0 hom.)
• Consequence: AKNAD1 NM_152763.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0630
• Publications: 2 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]

LOC105378891 (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=0.037880093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKNAD1	NM_152763.5	c.1912G>A	p.Ala638Thr	missense_variant	Exon 11 of 16	ENST00000370001.8	NP_689976.2
AKNAD1	NR_049760.2	n.2124G>A		non_coding_transcript_exon_variant	Exon 10 of 14
LOC105378891	XR_007066273.1	n.147+3511C>T		intron_variant	Intron 2 of 4
LOC105378891	XR_947687.3	n.122+3511C>T		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKNAD1	ENST00000370001.8	c.1912G>A	p.Ala638Thr	missense_variant	Exon 11 of 16	1	NM_152763.5	ENSP00000359018.3

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151380 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

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: 0.0000120 AC: 3 AN: 250980 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000206 AC: 3 AN: 1459842 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726244

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000673 AC: 3 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39070

South Asian (SAS) AF: 0.00 AC: 0 AN: 86034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111286

Other (OTH) AF: 0.00 AC: 0 AN: 60276

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151380 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73854

African (AFR) AF: 0.00 AC: 0 AN: 41298

American (AMR) AF: 0.0000663 AC: 1 AN: 15082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5018

South Asian (SAS) AF: 0.00 AC: 0 AN: 4738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67924

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1912G>A (p.A638T) alteration is located in exon 11 (coding exon 10) of the AKNAD1 gene. This alteration results from a G to A substitution at nucleotide position 1912, causing the alanine (A) at amino acid position 638 to be replaced by a threonine (T). 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	0.080
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.3
DANN	Benign	0.92
DEOGEN2	Benign	0.0025	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.52	T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.97	L;.;L
PhyloP100		-0.063
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.012
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.046	B;.;.
Vest4		0.038
MutPred		0.083		Gain of glycosylation at A638 (P = 0.0553);.;Gain of glycosylation at A638 (P = 0.0553);
MVP		0.014
MPC		0.030
ClinPred		0.021	T
GERP RS		0.99
Varity_R		0.033
gMVP		0.018
Mutation Taster		=96/4	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: rs775377275; hg19: chr1-109369851; COSMIC: COSV62197157;