12-110127445-A-C

Position:

• chr12-110127445-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014055.4(IFT81):​c.65A>C​(p.Asn22Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,608,994 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N22D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0027 (5 hom.)
• Consequence: IFT81 NM_014055.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 8.95

Genes affected

IFT81 (HGNC:14313): (intraflagellar transport 81) The protein encoded by this gene, together with IFT74, forms a tubulin-binding module of intraflagellar transport complex B. This module is involved in transport of tubulin within the cilium, and the encoded protein is required for ciliogenesis. Mutations in this gene are a cause of short-rib polydactyly syndromes. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022544831).
• BP6: Variant 12-110127445-A-C is Benign according to our data. Variant chr12-110127445-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 731781.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00153 (233/152312) while in subpopulation NFE AF= 0.00281 (191/68032). AF 95% confidence interval is 0.00248. There are 1 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT81	NM_014055.4	c.65A>C	p.Asn22Thr	missense_variant	2/19	ENST00000242591.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT81	ENST00000242591.10	c.65A>C	p.Asn22Thr	missense_variant	2/19	1	NM_014055.4	P1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152194 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00130 AC: 317 AN: 243004 Hom.: 1 AF XY: 0.00133 AC XY: 175 AN XY: 131510

Gnomad AFR exome AF: 0.000468

Gnomad AMR exome AF: 0.000836

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000204

Gnomad FIN exome AF: 0.0000934

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.00274 AC: 3990 AN: 1456682 Hom.: 5 Cov.: 30 AF XY: 0.00263 AC XY: 1908 AN XY: 724374

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.000865

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.0000939

Gnomad4 NFE exome AF: 0.00340

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152312 Hom.: 1 Cov.: 31 AF XY: 0.00125 AC XY: 93 AN XY: 74462

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00281

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00249 Hom.: 2

Bravo AF: 0.00171

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00125 AC: 152

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

IFT81-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.039	.;T;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.023	T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.8	L;L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.4	N;N;N;D
REVEL	Uncertain	0.36
Sift	Benign	0.30	T;T;T;T
Sift4G	Pathogenic	0.0	D;T;T;D
Polyphen		1.0	D;P;P;.
Vest4		0.80
MVP		0.86
MPC		0.31
ClinPred		0.057	T
GERP RS		6.1
Varity_R		0.26
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs151311859; hg19: chr12-110565250; COSMIC: COSV99656051; COSMIC: COSV99656051;