16-81042312-A-G

Position:

• chr16-81042312-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015251.3(ATMIN):​c.494A>G​(p.His165Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATMIN NM_015251.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.25

Genes affected

ATMIN (HGNC:29034): (ATM interactor) Enables dynein complex binding activity. Involved in positive regulation of transcription, DNA-templated. Located in nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATMIN	NM_015251.3	c.494A>G	p.His165Arg	missense_variant	3/4	ENST00000299575.5	NP_056066.2
ATMIN	NM_001300728.2	c.26A>G	p.His9Arg	missense_variant	3/4		NP_001287657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATMIN	ENST00000299575.5	c.494A>G	p.His165Arg	missense_variant	3/4	1	NM_015251.3	ENSP00000299575	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461512 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727088

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

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

Feb 12, 2024

The c.494A>G (p.H165R) alteration is located in exon 3 (coding exon 3) of the ATMIN gene. This alteration results from a A to G substitution at nucleotide position 494, causing the histidine (H) at amino acid position 165 to be replaced by an arginine (R). 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;.;D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.9	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D;.;.;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0060	D;.;.;D
Sift4G	Pathogenic	0.0	D;D;T;D
Polyphen		1.0	D;.;.;.
Vest4		0.89
MutPred		0.42		Gain of MoRF binding (P = 0.0065);.;.;.;
MVP		0.92
MPC		0.23
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.56
gMVP		0.85

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: rs1971048933; hg19: chr16-81075917;