1-246840937-A-C

Position:

• chr1-246840937-A-C

Variant summary

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

The NM_001323342.2(AHCTF1):​c.6670T>G​(p.Leu2224Val) 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. 13/21 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: 1.51

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=0.17711776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHCTF1	NM_001323342.2	c.6670T>G	p.Leu2224Val	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.6670T>G	p.Leu2224Val	missense_variant	36/36		NM_001323342.2	ENSP00000497061	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Aug 17, 2021

The c.6697T>G (p.L2233V) alteration is located in exon 36 (coding exon 36) of the AHCTF1 gene. This alteration results from a T to G substitution at nucleotide position 6697, causing the leucine (L) at amino acid position 2233 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;.;T
Eigen	Benign	0.032
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	.;.;M
MutationTaster	Benign	0.95	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.57	N;N;.
REVEL	Benign	0.083
Sift	Uncertain	0.011	D;D;.
Sift4G	Benign	0.15	T;T;.
Polyphen		0.95	P;.;P
Vest4		0.19
MutPred		0.18		.;.;Gain of MoRF binding (P = 0.0964);
MVP		0.47
MPC		0.89
ClinPred		0.68	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1659816925; hg19: chr1-247004239;