1-246840905-T-G

Position:

• chr1-246840905-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001323342.2(AHCTF1):​c.6702A>C​(p.Lys2234Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AHCTF1 NM_001323342.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.349

Genes affected

AHCTF1 (HGNC:24618): (AT-hook containing transcription factor 1) Predicted to enable DNA binding activity. Involved in nuclear pore complex assembly and regulation of cytokinesis. Located in nuclear membrane. Colocalizes with chromatin; kinetochore; and nuclear pore outer ring. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22229493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHCTF1	NM_001323342.2	c.6702A>C	p.Lys2234Asn	missense_variant	36/36	ENST00000648844.2	NP_001310271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHCTF1	ENST00000648844.2	c.6702A>C	p.Lys2234Asn	missense_variant	36/36		NM_001323342.2	ENSP00000497061	A2
AHCTF1	ENST00000326225.3	c.6729A>C	p.Lys2243Asn	missense_variant	36/36	1		ENSP00000355465	P2
AHCTF1	ENST00000470300.5	n.5234A>C		non_coding_transcript_exon_variant	26/26	1
AHCTF1	ENST00000366508.5	c.6807A>C	p.Lys2269Asn	missense_variant	36/36	5		ENSP00000355464	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jun 23, 2021

The c.6729A>C (p.K2243N) alteration is located in exon 36 (coding exon 36) of the AHCTF1 gene. This alteration results from a A to C substitution at nucleotide position 6729, causing the lysine (K) at amino acid position 2243 to be replaced by an asparagine (N). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;.;T
Eigen	Benign	0.050
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.5	.;.;M
MutationTaster	Benign	0.83	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N;N;.
REVEL	Benign	0.085
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.014	D;D;.
Polyphen		0.99	D;.;D
Vest4		0.20
MutPred		0.25		.;.;Loss of methylation at K2234 (P = 0.0109);
MVP		0.27
MPC		0.80
ClinPred		0.85	D
GERP RS		-0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.095
gMVP		0.18

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: rs1659813196; hg19: chr1-247004207;