chr8-144476070-A-C

Variant names:

• chr8-144476070-A-C
• rs750472
• ENST00000920082.1:c.-1210A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000920082.1(PPP1R16A):​c.-1210A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 314,232 control chromosomes in the GnomAD database, including 38,518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19244 hom., cov: 32)
  • Exomes 𝑓: 0.48 (19274 hom.)
• Consequence: PPP1R16A ENST00000920082.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.68
• Publications: 28 publications found

Genes affected

PPP1R16A (HGNC:14941): (protein phosphatase 1 regulatory subunit 16A) Myosin light chain kinase and phosphatase (MLCP) complexes control the phosphorylation states of regulatory myosin light chains, which is crucial for muscle and intracellular movement. MLCPs typically contain a catalytic protein phosphatase 1 (PP1c) subunit, a myosin phosphatase targeting (MYPT) subunit, and another smaller subunit. The protein encoded by this gene represents an MYPT subunit, which is responsible for directing PP1c to its intended targets. However, while the phosphorylation of other MYPT members results in PP1c inactivation, phosphorylation of the encoded protein by protein kinase A results in PP1c activation. [provided by RefSeq, Jan 2020]

FOXH1 (HGNC:3814): (forkhead box H1) FOXH1 encodes a human homolog of Xenopus forkhead activin signal transducer-1. FOXH1 protein binds SMAD2 and activates an activin response element via binding the DNA motif TGT(G/T)(T/G)ATT. [provided by RefSeq, Jul 2008]

FOXH1 Gene-Disease associations (from GenCC):

• congenital heart malformation

  Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 8-144476070-A-C is Benign according to our data. Variant chr8-144476070-A-C is described in ClinVar as Benign. ClinVar VariationId is 362288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000920082.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXH1	NM_003923.3	MANE Select	c.-314T>G		upstream_gene	N/A	NP_003914.1	O75593

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R16A	ENST00000920082.1		c.-1210A>C		5_prime_UTR	Exon 1 of 12	ENSP00000590141.1
	FOXH1	ENST00000377317.5	TSL:1 MANE Select	c.-314T>G		upstream_gene	N/A	ENSP00000366534.4	O75593
	FOXH1	ENST00000935088.1		c.-314T>G		upstream_gene	N/A	ENSP00000605147.1

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75490 AN: 151722 Hom.: 19218 Cov.: 32

Gnomad AFR AF: 0.559

Gnomad AMI AF: 0.660

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.482

GnomAD4 exome AF: 0.480 AC: 77898 AN: 162394 Hom.: 19274 Cov.: 0 AF XY: 0.481 AC XY: 39277 AN XY: 81730

African (AFR) AF: 0.567 AC: 2961 AN: 5220

American (AMR) AF: 0.379 AC: 1753 AN: 4620

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 3135 AN: 6544

East Asian (EAS) AF: 0.281 AC: 4169 AN: 14828

South Asian (SAS) AF: 0.456 AC: 703 AN: 1540

European-Finnish (FIN) AF: 0.511 AC: 6898 AN: 13504

Middle Eastern (MID) AF: 0.569 AC: 511 AN: 898

European-Non Finnish (NFE) AF: 0.503 AC: 52372 AN: 104146

Other (OTH) AF: 0.486 AC: 5396 AN: 11094

GnomAD4 genome AF: 0.498 AC: 75565 AN: 151838 Hom.: 19244 Cov.: 32 AF XY: 0.493 AC XY: 36552 AN XY: 74194

African (AFR) AF: 0.559 AC: 23139 AN: 41358

American (AMR) AF: 0.388 AC: 5926 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1715 AN: 3470

East Asian (EAS) AF: 0.289 AC: 1489 AN: 5156

South Asian (SAS) AF: 0.422 AC: 2031 AN: 4812

European-Finnish (FIN) AF: 0.510 AC: 5395 AN: 10570

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34079 AN: 67884

Other (OTH) AF: 0.484 AC: 1021 AN: 2108

Alfa AF: 0.492 Hom.: 26638

Bravo AF: 0.489

Asia WGS AF: 0.405 AC: 1409 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Holoprosencephaly sequence (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.23
DANN	Benign	0.40
PhyloP100		-2.7
PromoterAI		0.031	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs750472; hg19: chr8-145701453; COSMIC: COSV56763057; COSMIC: COSV56763057;