NM_001082486.2:c.741G>T

Variant names:

• chr16-67658721-C-A
• rs776468683
• NM_001082486.2:c.741G>T

Variant summary

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

The NM_001082486.2(ACD):​c.741G>T​(p.Gln247His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,714 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. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q247K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ACD NM_001082486.2 missense, splice_region
• Scores: Splicing: ADA: 0.00007098
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• Publications: 0 publications found

Genes affected

ACD (HGNC:25070): (ACD shelterin complex subunit and telomerase recruitment factor) This gene encodes a protein that is involved in telomere function. This protein is one of six core proteins in the telosome/shelterin telomeric complex, which functions to maintain telomere length and to protect telomere ends. Through its interaction with other components, this protein plays a key role in the assembly and stabilization of this complex, and it mediates the access of telomerase to the telomere. Multiple transcript variants encoding different isoforms have been found for this gene. This gene, which is also referred to as TPP1, is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I. [provided by RefSeq, Jul 2008]

ACD Gene-Disease associations (from GenCC):

• dyskeratosis congenita, autosomal dominant 6

  Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hereditary isolated aplastic anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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=0.056794286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACD	NM_001082486.2	c.741G>T	p.Gln247His	missense_variant, splice_region_variant	Exon 8 of 12	ENST00000620761.6	NP_001075955.2
ACD	NM_022914.3	c.732G>T	p.Gln244His	missense_variant, splice_region_variant	Exon 8 of 12		NP_075065.3
ACD	NM_001410884.1	c.741G>T	p.Gln247His	missense_variant, splice_region_variant	Exon 8 of 11		NP_001397813.1
ACD	XR_429728.4	n.797G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACD	ENST00000620761.6	c.741G>T	p.Gln247His	missense_variant, splice_region_variant	Exon 8 of 12	1	NM_001082486.2	ENSP00000478084.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458714 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 725314

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 85872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110190

Other (OTH) AF: 0.00 AC: 0 AN: 60226

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	.;T;T;T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.56	T;T;.;T;T;.
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.057	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;L;.;.;.;.
PhyloP100		-0.018
PrimateAI	Benign	0.31	T
REVEL	Benign	0.031
Sift4G	Uncertain	0.011	.;D;D;.;D;.
Polyphen		0.015, 0.026	.;B;.;.;.;B
Vest4		0.24, 0.21, 0.21
MutPred		0.21		.;Loss of glycosylation at P338 (P = 0.2288);.;.;.;.;
MVP		0.20
MPC		0.091
ClinPred		0.044	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
dbscSNV1_RF	Benign	0.086
SpliceAI score (max)		0.020		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: rs776468683; hg19: chr16-67692624;